CN104144930A - New indolizine derivatives, method for preparing same and pharmaceutical compositions containing same - Google Patents

New indolizine derivatives, method for preparing same and pharmaceutical compositions containing same Download PDF

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CN104144930A
CN104144930A CN201380006468.5A CN201380006468A CN104144930A CN 104144930 A CN104144930 A CN 104144930A CN 201380006468 A CN201380006468 A CN 201380006468A CN 104144930 A CN104144930 A CN 104144930A
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phenyl
dihydro
methyl
preparation example
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CN104144930B (en
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T·勒迪加尔
P·卡萨拉
J-B·斯塔克
J-M·贺琳
J·E·P·戴维森
J·B·穆雷
C·J·格拉哈姆
I-J·陈
O·热内斯特
J·希克曼
S·德皮尔
A·勒蒂朗
M·尼耶格斯
G·德南特伊
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Novartis AG
Laboratoires Servier SAS
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Novartis AG
Laboratoires Servier SAS
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
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Abstract

Compounds of formula (I) wherein Ra, Rb, Rc, Rd, R1, R2, R3, R4, R5; X, Y and Het are as defined in the description.

Description

New indolizine compounds, their preparation method and the pharmaceutical composition that comprises them
The present invention relates to new indolizine compounds, their preparation method and the pharmaceutical composition that comprises them.
The compounds of this invention is new and in apoptosis and cancer field, has very valuable pharmacological property.
Apoptosis or apoptosis are for fetal development and maintain that to organize homeostasis be vital physiological process.
The necrocytosis of apoptosis type relates to for example nucleus compression of morphological change, DNA is cracked; Also relate to the activation of for example Caspase of Biochemical Phenomena, it causes the damage to cell important structure component, thereby inducing cell disintegrates and be dead.The adjusting of apoptosis process be activation complicated and that relate to several Cellular Signaling Transduction Mediated paths or inhibition (people such as Cory S., Nature Review Cancer, 2002, 2, 647-656).
In some pathology, relate to apoptotic not normal.The apoptosis raising is relevant with neurodegenerative disease for example Parkinson's disease, alzheimer's disease and local asphyxia.On the contrary, the defect that apoptosis is realized in the development of the drug resistance of cancer and they, play a significant role in autoimmune disease, inflammatory diseases and virus infection.Therefore, lack a kind of phenotypic characteristic people such as (, Cell2000,100,57-70) Hanahan D. that apoptosis is cancer.
The anti-apoptotic protein of Bcl-2 family is relevant with a lot of pathology.In very eurypalynous cancer, described the participation of the protein of Bcl-2 family, described cancer is colorectal carcinoma, breast cancer, small cell lung cancer, nonsmall-cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukemia, follicular lymphoma, myelomatosis, prostate cancer etc. such as.The clinical prognosis that participates in tumour formation, chemotherapy resistance and invasive cancer patient is expressed in crossing of the anti-apoptotic protein of Bcl-2 family.Therefore, there are treatment needs for the compound of anti-apoptotic activity of the protein that suppresses Bcl-2 family.
Except being new compound, the compounds of this invention has short apoptosis characteristic, for example makes to relate in treatment cancer and immunity and autoimmune disease in the pathology of apoptosis defect to use them to become possibility.
The present invention relate more particularly to formula (I) compound, their enantiomer and diastereomer with and with the additive salt of pharmaceutically acceptable acid or alkali:
Wherein:
◆ X and Y represent carbon atom or nitrogen-atoms, should be understood that they can not represent two carbon atoms or two nitrogen-atoms simultaneously,
◆ group het part represent aromatics or the non-aromatic ring of the optional replacement being formed by 5,6 or 7 ring memberses, except the nitrogen-atoms that X or Y represent, it can comprise 1 to 3 heteroatoms independently selected from oxygen, sulphur and nitrogen, should be understood that described nitrogen can be by (the C of hydrogen atom, linearity or branch 1-C 6) alkyl or group that group-C (O)-O-Alk represents replace, wherein Alk is linearity or the (C of branch 1-C 6) alkyl,
◆ R 1and R 2represent independently of one another (the C of hydrogen atom or linearity or branch 1-C 6) alkyl,
Or R 1and R 2form by 4 to 7 Heterocyclylalkyls that ring members forms with the nitrogen-atoms with them, except nitrogen-atoms, it can comprise other oxygen, sulphur, the SO of being selected from 2with the heteroatoms of NR, wherein R represents the (C of hydrogen atom, linearity or branch 1-C 6) alkyl, (C 1-C 6) (the C of alkyl sulphonyl, linearity or branch 1-C 6) multi-haloalkyl or group-C (O)-O-Alk, Alk is linearity or the (C of branch 1-C 6) alkyl,
◆ R 3represent (the C of linearity or branch 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, cycloalkyl, (C 4-C 10) cycloalkyl-(C 1-C 6) alkyl, wherein alkyl can be linear or branch, aryl or heteroaryl,
◆ R 4represent (the C of aryl, heteroaryl, cycloalkyl or linearity or branch 1-C 6) alkyl,
◆ R 5represent hydrogen atom or halogen atom,
◆ R a, R b, R cand R drepresent independently of one another (the C of hydrogen atom, halogen atom, linearity or branch 1-C 6) (the C of alkyl, linearity or branch 1-C 6) (the C of alkoxyl group, hydroxyl, linearity or branch 1-C 6) multi-haloalkyl or trifluoromethoxy, or paired (R a, R b), (R b, R c) or (R c, R d) one of substituting group form by 5 to 7 rings that ring members forms with together with carbon atom with them, it can comprise 1 to 3 heteroatoms that is selected from oxygen, sulphur and nitrogen, should be understood that described nitrogen can be by (the C of hydrogen atom, linearity or branch 1-C 6) alkyl or group that group-C (O)-O-Alk represents replace, wherein Alk is linearity or the (C of branch 1-C 6) alkyl, the one or more carbon atoms that should be understood that ring defined above can be deuterates,
Should be understood that:
-" aryl " represents phenyl, naphthyl, xenyl or indenyl,
-" heteroaryl " represents any monocycle or the bicyclic groups that are made up of 5 to 10 ring memberses, there is at least one aromatics part and comprise 1 to 3 heteroatoms that is selected from oxygen, sulphur and nitrogen,
-" cycloalkyl " represents any monocycle or the non-aromatic carbocyclic ring of two rings that comprise 4 to 10 ring memberses,
It is possible being replaced by 1 to 3 group for defined alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl, and described group is selected from the linearity of optional replacement or the (C of branch 1-C 6) alkyl, (C 3-C 6) (the C of volution, linearity or branch 1-C 6) alkoxyl group, (C 1-C 6) alkyl-S-, hydroxyl, oxo (or suitably N-oxide compound), nitro, cyano group ,-COOR ', NR ' R ", (C of linearity or branch 1-C 6) multi-haloalkyl, trifluoromethoxy, (C 1-C 6) alkyl sulphonyl or halogen, should be understood that R ' and R " represent independently of one another (the C of hydrogen atom or linearity or branch 1-C 6) alkyl,
For defined above it is possible that the Het part of group is replaced by group, and described group is selected from the (C of linearity or branch 1-C 6) alkyl, hydroxyl, NR 1' R 1" and halogen, should be understood that R 1' and R 1" with radicals R mentioned above ' and R " there is identical definition.
In pharmaceutically acceptable acid, do not represent any restriction, what can mention is hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, propanedioic acid, succsinic acid, pentanedioic acid, fumaric acid, tartrate, toxilic acid, citric acid, xitix, oxalic acid, methylsulfonic acid, dextrocamphoric acid etc.
In pharmaceutically acceptable alkali, without any restriction, what can mention is sodium hydroxide, potassium hydroxide, triethylamine, TERTIARY BUTYL AMINE etc.
Group:
Advantageously represent one of following groups: optionally replaced by hydroxyl 5,6,7,8-indolizine, indolizine, 1,2,3,4-Pyrrolidine also [1,2-a] pyrazine, 3,4-pyrrolin is [1,2-a] pyrazine-2 (1H)-t-butyl formate, 3 also, 4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine, optionally replaced by hydroxyl 2,3-dihydro-1H-pyrrolizine (pyrrolizine), 6,7,8,9-tetrahydrochysene-5H-pyrrolo-[1,2-a] azepine or pyrrolo-[1,2-a] pyrazine.
In preferred compound of the present invention, R 1and R 2represent optionally by the alkyl of methoxy substitution separately, or R 1and R 2form Heterocyclylalkyl with the nitrogen-atoms with them, be selected from following groups: optionally by the (C of one or more linearities or branch 1-C 6) alkyl replace morpholine, morpholine oxide (oxidomorpholine), thiomorpholine, 1,1-dioxide, 1,4-oxa-azepan, 3-methoxyl group tetramethyleneimine, 3,3-bis-fluoropyrrolidines, 3-methoxyl group azetidine, 3-fluorine azetidine, oxo piperazine or piperazine, latter two group is by (the C of linearity or branch 1-C 6) (the C of alkyl, linearity or branch 1-C 6) multi-haloalkyl or methyl sulphonyl replacement.
Preferably, R aand R drepresent separately hydrogen atom, and (R b, R c) form DOX group (one of them carbon atom is optionally deuterate), Isosorbide-5-Nitrae-dioxane group, Isosorbide-5-Nitrae-Dioxepane group with together with carbon atom with them, or R a, R cand R drepresent separately hydrogen atom, and R brepresent halogen, methyl, methoxyl group, oxyethyl group, trifluoromethyl or trifluoromethoxy.
Preferred radicals R 4the fluoro-4-hydroxy phenyl of 4-hydroxy phenyl, 3-or 5-hydroxy pyrimidine group.
In preferred compound, R 3represent to be selected from following group: phenyl, indoles, indoline, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzo piperazine, indane, 1H-indazole, 1H-pyrrolo-[2,3-b] pyridine, pyrimidine, cyclobutylmethyl, cyclopropyl methyl, 1H-pyrazoles, pyridine, pyridazine, those groups optionally have one or more substituting groups, and described substituting group is selected from the (C of halogen, linearity or branch 1-C 6) (the C of alkyl, cyano group and linearity or branch 1-C 6) alkoxyl group.
List preferred the compounds of this invention below:
-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
The chloro-2-[((3S of-3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-3-{2,2-bis-deuteriums-6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-5,6,7,8-indolizine-1-methane amide
-N-(4-hydroxy phenyl)-3-{7-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine methane amide,
-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-[(4-methyl isophthalic acid-piperazinyl) methyl]-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine methane amide
-N-[4-(hydroxyl) phenyl]-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-1-indolizine methane amide
The chloro-2-[((3S of-3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-1-indolizine methane amide
The chloro-2-[((3S of-6-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(the fluoro-4-aminomethyl phenyl of 3-)-N-(4-hydroxy phenyl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-methane amide,
-3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-pyrazoles-4-yl)-5,6,7,8-indolizine-1-methane amide
-N-(the fluoro-4-aminomethyl phenyl of 3-)-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-[4-(hydroxyl) phenyl]-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
The chloro-2-[((3S of-3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine methane amide
The chloro-2-[((3S of-3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-1-indolizine methane amide
The chloro-2-[((3S of-6-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-phenyl-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-methane amide,
-N-(3-fluorophenyl)-N-(4-hydroxy phenyl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-5,6,7,8-indolizine-1-methane amide
Their enantiomer and diastereomer with and with the additive salt of pharmaceutically acceptable acid or alkali.
The invention still further relates to the method for preparation formula (I) compound, the method is characterized in that formula (II) compound is used as to raw material:
Wherein R a, R b, R cand R dit is defined suc as formula (I),
Formula (II) compound is carried out in moisture or organic medium under the existence of palladium catalyst, alkali, phosphine and formula (III) compound to Heck reaction:
Wherein radicals X, Y and Het are defined suc as formula (I),
Obtain formula (IV) compound:
Wherein R a, R b, R c, R d, X, Y and Het defined suc as formula (I),
The aldehyde functional group of formula (IV) compound is oxidized to carboxylic acid, forms formula (V) compound:
Wherein R a, R b, R c, R d, X, Y and Het defined suc as formula (I),
Then, formula (V) compound and formula (VI) compound are carried out to peptide coupling:
Wherein R 1, R 2and R 5it is defined suc as formula (I),
Obtain formula (VII) compound:
Wherein R a, R b, R c, R d, R 1, R 2, R 5, X, Y and Het defined suc as formula (I),
By the ester functional group hydrolysis of formula (VII) compound, obtain carboxylic acid or corresponding carboxylate salt, with amine NHR 3r 4(wherein R 3and R 4there is the implication identical with formula (I)) can be translated into acid derivative before coupling, for example acyl chlorides or corresponding acid anhydrides, obtain formula (I) compound,
Formula (I) compound can be according to conventional isolation technique purifying, if needed, itself and pharmaceutically acceptable acid or alkali is converted into additive salt, and the isomer that is it by its optionally separating according to conventional isolation technique,
Should be understood that, in the process of aforesaid method, be considered to suitable in, some group (hydroxyl, the amino of initial reagent or synthetic intermediate ...) can be according to synthetic needs protected and deprotection subsequently,
More specifically, as amine NHR 3r 4radicals R 3or R 4one of while being replaced by hydroxy functional group; with the carboxylic acid or its corresponding acid derivative coupling of formula (VII) compound formation before; the latter can carry out protective reaction in advance; formula (I) compound of the protection producing carries out deprotection reaction subsequently, is then optionally converted into one of additive salt with pharmaceutically acceptable acid or alkali.
Formula (II), (III), (VI) compound and amine NHR 3r 4or commercially available, or can use the conventional chemical reaction described in document to obtain by those skilled in the art.
The pharmaceutical research of the compounds of this invention has shown that they have short apoptosis characteristic.In cancer cells, the ability of activating cells apoptotic process is to have important treatment benefit in treatment cancer and immunity and autoimmune disease.
More particularly, the compounds of this invention can be used for treating the cancer of chemotherapy or radiotherapy opposing, and can be used for malignant hematologic disease and small cell lung cancer.
Described cancer therapy does not represent any restriction, and what can mention is bladder cancer, the cancer of the brain, breast cancer and uterus carcinoma, chronic lymphoid leukemia, colorectal carcinoma, esophagus cancer and liver cancer, lymphoblast leukemia, follicular lymphoma, melanoma, malignant hematologic disease, myelomatosis, ovarian cancer, nonsmall-cell lung cancer, prostate cancer and small cell lung cancer.
The invention still further relates to the pharmaceutical composition that comprises at least one formula (I) compound and one or more pharmaceutically acceptable vehicle.
In pharmaceutical composition of the present invention, more particularly can mention be suitable for oral, non-enteron aisle, nose, use through skin or transdermal, rectum, through tongue, through eye or breathing those, particularly tablet or dragee, Sublingual tablet, sachet, cartridge bag, capsule, glossettes, lozenge, suppository, ointment, ointment, skin gel agent and drinkable or injectable ampoule.
Dosage is according to the character of patient's sex, age and body weight, route of administration, treatment indication or any associated treatment and difference, and in one or many is used, the scope of every 24 hours is 0.01mg to 1g.
In addition, the invention still further relates to the combination of formula (I) compound and carcinostatic agent, described carcinostatic agent be selected from there is genotoxic promoting agent, mitotic division poisonous substance, antimetabolite, proteasome inhibitor, kinase inhibitor and antibody, and the invention still further relates to the pharmaceutical composition and their purposes in the medicine for the preparation for the treatment of cancer that comprise this type combination.
The compounds of this invention can also be used for and radiotherapy treatment of cancer with combinations.
Following preparation example and embodiment illustrate the present invention, but do not limit the present invention in any way.
preparation example 1: 6-[1-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base]-1,3-benzo dioxole-5-formic acid
steps A: 1-formyl radical-Pipecolic Acid
In the 300mL formic acid solution of 40g2-piperidine carboxylic acid racemic mixture (0.310mmol), drip 200mL (2.15mmol) diacetyl oxide at 0 DEG C.Then entirety is stirred and spent the night in envrionment temperature.Then reaction mixture is cooled to 0 DEG C, by adding 250mL water to be hydrolyzed and stirring half hour at 0 DEG C, is concentrated into afterwards dry.Thus obtained oily matter is dissolved in to 200mL methyl alcohol, is then concentrated into dry.Title product obtains with oily matter form, productive rate 98%.Without being further purified, it is directly used in next step.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K): 13.0 (m, 1H OH); (8.0-8.05 2s, 1H aldehyde); 4.9-4.5 (2d, the α of 1H N and COOH); 4.1-2.6 (m, the α of 2H N); 2.2-1.2 (m, 6H piperidines).
IR: ν :-OH:2000-3000cm -1acid; ν: >C=O1703cm -1broadband.
step B: 5,6,7,8-tetrahydrochysene-1-indolizine methyl-formiate
In the 65mL dichloroethane solution of the carboxylic acid (63.6mmol) obtaining to 10g steps A, add successively 13.4g toluene sulfonyl chloride (70.4mmol), 11.5mL2-chloracrylic acid methyl esters (113.5mmol), then drip 17.8mL N, N, N-triethylamine (127.2mmol).Then by reaction mixture refluxed 1.5 hours.Then be placed on envrionment temperature, then add 5mL2-chloracrylic acid methyl esters (48.9mmol), and drip 9mL N, N, N-triethylamine (64mmol).By entirety heated overnight under refluxing.
Subsequently reaction mixture is diluted with methylene dichloride, use successively 1N HCl solution, saturated NaHCO 3solution washing, then with saturated NaCl solution washing until obtain neutral pH.Then by organic phase through MgSO 4dry, filter, be concentrated into dry, and by silica gel chromatography purifying (heptane/AcOEt gradient).Title product obtains with oily matter form.
1h-NMR: δ (400MHz; CDCl 3; 300 ° of K): 6.55-6.40 (d, 2H, indolizine); 3.91 (t, 3H, methyl esters); 3.78 (s, 3H, indolizines); 3.08 (t, 2H, indolizines); (1.95-1.85 m, 4H, indolizine)
IR: ν: >C=O1692cm -1ester.
step C: 3-(6-formyl radical-1,3-benzo dioxole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine methyl-formiate
The 12mL N of the ester (35.7mmol) obtaining to 6.4g step B, in N-dimethylacetamide solution, add successively 12.3g6-bromo-1,3-benzo dioxole-5-formaldehyde (53.6mmol) and 7g potassium acetate (71.4mmol) then stir entirety 20 minutes under argon gas.Add again 1.3g palladium catalyst PdCl 2(PPh 3) 2(1.8mmol).Subsequently reaction mixture is heated 1 hour at 130 DEG C, add wherein afterwards 139 μ L H 2o.Keep heated overnight at uniform temp.Mixture is returned to envrionment temperature, then dilute with AcOEt.Add carbo animalis (every gram of product 2g), and entirety is stirred 1 hour in envrionment temperature, then filter.Then organic phase is washed with water, through dried over mgso and be concentrated into dry.By thus obtained crude product purifying (heptane/AcOEt gradient) on silica gel.Title product is to obtain with oily matter form.
1h-NMR: δ: (400MHz; Dmso-d6; 353 ° of K): 9.65 (s, 1H, H aldehyde); 7.3-7.15 (2s, 2H, H aromatics); (6.45 s, 1H indolizine); 6.20 (s, 2H m methylene radical dioxy bases); 3.70 (s, 3H, methyl esters); 3.5-4.0 (m, 2H, indolizine); 3.05 (m, 2H, indolizines); 1.85 (m, 4H, indolizines)
IR: ν: >C=O1695cm -1ester; ν: >C=O1674cm -1
step D: 6-[1-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base]-1,3-benzo dioxole-5-formic acid
Preparation is included in the solution of the 2-methyl-2-butene of compound (10.3mmol) that 3.37g step C in 9.3mL acetone obtains and 8.8mL (80.24mmol), by this solution 0 DEG C of placement.Drip 9.3mL and comprise 3.3g NaClO 2(36.05mmol) with 3.6g Na 2pO 4(25.75mmol) aqueous solution of mixture.Subsequently entirety is stirred 7 hours in envrionment temperature.Then reaction mixture is concentrated to remove acetone.Then filter the solid obtaining, wash with water, then spend the night 40 DEG C of vacuum-dryings.Title product is to obtain with solid form, and it uses without being further purified subsequently.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K): 12.10 (m, 1H, H carboxylic acids); 7.40-6.88 (2s, 2H, H aromatics); 6.20 (s, 1H, H indolizines); 6.18 (s, 2H, H methylene radical dioxy bases); (3.70 s, 3H, methyl esters); (3.55 t, 2H, indolizine); (3.00 t, 2H, indolizine); 1.80 (m, 4H, H indolizines)
IR: ν :-OH:3000-2000cm -1acid; ν: >C=O1686-1676cm -1ester+acid; ν: >C=C<1608cm -1.
preparation example 2: the bromo-2-[1-of 4-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base] phenylformic acid
The method is as the method for preparation example 1, replaces step C 6-used bromo-1 with 2,4-dibromo benzaldehyde, 3-benzo dioxole-5-formaldehyde.The mixture that obtains two kinds of regional isomers, is passed through chromatographic separation.
preparation example 3: the chloro-2-[1-of 4-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base] phenylformic acid
The method is as the method for preparation example 1, replaces step C 6-used bromo-1 with the bromo-4-chlorobenzaldehyde of 2-, 3-benzo dioxole-5-formaldehyde.
preparation example 4: the fluoro-2-[1-of 4-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base] phenylformic acid
The method is as the method for preparation example 1, replaces step C 6-used bromo-1 with the bromo-4-fluorobenzaldehyde of 2-, 3-benzo dioxole-5-formaldehyde.
preparation example 5: 8-[1-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base]-3,4-dihydro-2H-1,5-benzo dioxa -7-formic acid
The method is as the method for preparation example 1, bromo-3 with 8-, 4-dihydro-2H-1,5-benzo dioxa -7-formaldehyde replaces step C 6-used bromo-1,3-benzo dioxole-5-formaldehyde.
preparation example 6:4-methoxyl group-2-[1-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base] phenylformic acid
The method is as the method for preparation example 1, replaces 6-bromo-1 with the bromo-4-methoxybenzaldehyde of 2-, 3-benzo dioxole-5-formaldehyde.
preparation example 7:7-[1-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base]-2,3-dihydro-Isosorbide-5-Nitrae-benzo two alkene-6-formic acid
The method is as the method for preparation example 1, bromo-2 with 7-, 3-dihydro-Isosorbide-5-Nitrae-benzo two alkene-6-formaldehyde replaces step C 6-used bromo-1,3-benzo dioxole-5-formaldehyde.
preparation example 8:4-oxyethyl group-2-[1-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base] phenylformic acid
The method is as the method for preparation example 1, replaces step C 6-used bromo-1 with the bromo-4-ethoxy-benzaldehyde of 2-, 3-benzo dioxole-5-formaldehyde.
preparation example 9:2,2-, bis-deuteriums-6-[1-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base]-1,3-benzo dioxole-5-formic acid
steps A: 2,2-, bis-deuterium-1,3-benzo dioxole-5-formaldehyde
To 30g3, in the 110mL anhydrous DMF solution of 4-Dihydroxy benzaldehyde (217mmol), add successively the methylene dichloride (347mmol) of 114g cesium carbonate (347mmol) and 22mL bis-deuterates.Subsequently reaction mixture is stirred and spent the night in envrionment temperature.After the insoluble part of diatomite filtration, residue filtrate, again by adding 200mL water to be hydrolyzed, is then extracted with ethyl acetate.Then merge organic phase, with saturated LiCl solution washing, then through MgSO 4dry.Be concentrated into dry after, by residue by silica gel chromatography purifying (sherwood oil/AcOEt gradient).Title product is to obtain with solid form.
1h-NMR: δ: (400MHz; Dmso-d6; 300 ° of K): 9.8 (s, 1H, H aldehyde); 7.4-6.95 (m, 3H, H aromatics)
IR: ν: C=O aldehyde: 1670cm -1.
step B: 6-is bromo-2,2-bis-deuterium-1,3-benzo dioxole-5-formaldehyde
In the 100mL methanol solution of the compound (65.7mmol) obtaining to the 10g steps A that is cooled to 0 DEG C, drip the 10mL methanol solution of 3.7mL bromine (1.1 molar equivalent).Subsequently entirety is stirred and spent the night in envrionment temperature.Reaction mixture is concentrated into dry, then soluble in water.After stirring, filter the solid producing and be dried.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K): 10.2 (s, 1H, H aldehyde); 7.4 (s, 1H, H aromatics); 7.05 (s, 1H, H aromatics)
IR: ν: C=O aldehyde: 1670cm -1; C=C aromatics: 1611cm -1.
step C: 2,2-, bis-deuteriums-6-[1-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base]-1,3-benzo dioxole-5-formic acid
The scheme that the method is described as the step C of preparation example 1 and D, bromo-2 with 6-, 2-bis-deuterium-1,3-benzo dioxole-5-formaldehyde replaces step C 6-used bromo-1,3-benzo dioxole-5-formaldehyde.
preparation example 10:2-[1-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base]-4-(trifluoromethyl)-phenylformic acid
The scheme that the method is described as preparation example 1, replaces step C 6-used bromo-1 with the bromo-4-of 2-(trifluoromethyl) phenyl aldehyde, 3-benzo dioxole-5-formaldehyde.
preparation example 11:2-[1-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base]-4-(trifluoromethoxy) phenylformic acid
The scheme that the method is described as preparation example 1, replaces step C 6-used bromo-1 with the bromo-4-of 2-(trifluoromethoxy) phenyl aldehyde, 3-benzo dioxole-5-formaldehyde.
preparation example 12:2-[1-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-3-indolizine base] phenylformic acid
The scheme that the method is described as preparation example 1, replaces step C 6-used bromo-1 with 2-bromobenzaldehyde, 3-benzo dioxole-5-formaldehyde.
preparation example 13:6-[1-(methoxycarbonyl)-3-indolizine base]-1,3-benzo dioxole-5-formic acid
steps A: 1-(carboxyl methyl)-1,2-dichloropyridine hydrobromate
In the 120mL ethyl acetate solution of 16.2mL pyridine (200mmol), add 27.8g (200mmol) bromoacetic acid in batches.Subsequently entirety is stirred and spent the night in envrionment temperature.Filter thus obtained throw out, then with cold ethyl acetate washing.After dry, title product is to obtain with powder type, and it is directly used in next step.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K): 9.15 (d, 2H, H aromatics pyridines)); 8.7 (t, 1H, H aromatics); 8.25 (t, 2H, H aromatics); 5.65 (s, 2H, H CH 2cOOH)
IR: ν: C=O:1732cm -1;-OH acid: 2800cm -1.
step B: 1-indolizine methyl-formiate
The pyridine obtaining to 6.55g steps A in the 240mL toluene suspension of salt (30mmol), add successively 16.7mL methyl acrylate (150mmol), 4.2mL triethylamine (30mmol), then add 20.9g MnO in batches 2(240mmol).Subsequently entirety is heated 3 hours at 90 DEG C.After cooling, reaction mixture is filtered and is concentrated into dry through diatomite cake.By title product by silica gel purification with oily matter isolated in form (heptane/AcOEt gradient: 0-10%), its crystallization when cooling.
1h-NMR: δ (300MHz; Dmso-d6; 300 ° of K): 8.5 (d, 1H, H indolizine); 8.05 (d, 1H, H indolizine); 7.6 (s, 1H, H indolizine); 7.15 (m, 2H, H indolizine); 6.85 (m, 1H, H indolizine); 4.25 (q, 2H ,-C (O) CH 2cH 3); 1.35 (t, 3H ,-C (O) CH 2cH 3)
IR: ν: C=O ester: 1675cm -1; C=C aromatics: 1634cm -1
step C: 6-[1-(methoxycarbonyl)-3-indolizine base]-1,3-benzo dioxole-5-formic acid
The method is as the scheme of describing in the step C of preparation example 1 and D.
preparation example 14:the chloro-2-[1-of 4-(methoxycarbonyl)-3-indolizine base] phenylformic acid
1-indolizine methyl-formiate is to form according to the method for describing in the steps A of preparation example 13 and B.Obtain title product according to the scheme described in the step C of preparation example 1 and D subsequently, replace step C 6-used bromo-1 with the bromo-4-chlorobenzaldehyde of 2-, 3-benzo dioxole-5-formaldehyde.
preparation example 15:7-[1-(methoxycarbonyl)-3-indolizine base]-2,3-dihydro-Isosorbide-5-Nitrae-benzo two alkene-6-formic acid
1-indolizine methyl-formiate is to form according to the method for describing in the steps A of preparation example 13 and B.Obtain title product according to describing in the step C of preparation example 1 and D subsequently, bromo-2 with 7-, 3-dihydro-Isosorbide-5-Nitrae-benzo two alkene-6-formaldehyde replaces step C 6-used bromo-1,3-benzo dioxole-5-formaldehyde.
preparation example 16:4-methoxyl group-2-[1-(methoxycarbonyl)-3-indolizine base] phenylformic acid
1-indolizine methyl-formiate is to form according to the method for describing in the steps A of preparation example 13 and B.Obtain title product according to the scheme described in the step C of preparation example 1 and D subsequently, replace step C 6-used bromo-1 with the bromo-4-methoxybenzaldehyde of 2-, 3-benzo dioxole-5-formaldehyde.
preparation example 17:6-[2-(tert-butoxycarbonyl)-8-(methoxycarbonyl)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine-6-yl also]-1,3-benzo dioxole-5-formic acid
steps A: 4-formyl radical-1,3-piperazine dioctyl phthalate 1-tert-butyl ester 3-methyl esters
In the 520mL anhydrous aether solution of Pentafluorophenol, add successively 49g1-ethyl-3-(3 '-dimethylaminopropyl)-carbodiimide (286mmol) and 12mL formic acid (312mmol) at 0 DEG C in batches.Entirety is stirred 2 hours in envrionment temperature.Add subsequently 32g1, the 520mL CH of 3-piperazine dioctyl phthalate 1-tert-butyl ester 3-methyl esters (130mmol) and 18mL triethylamine (130mmol) mixture 2cl 2solution.Entirety is stirred and spent the night in envrionment temperature.By reaction mixture with 1N HCl aqueous hydrolysis and use CH 2cl 2extraction.Merge subsequently organic phase, then use saturated NaHCO 3solution washing, then uses saturated NaCl solution washing until neutrality.Through MgSO 4dry, filter and be concentrated into dry after, product is separated to (sherwood oil/AcOEt gradient: 0-30%) by silica gel chromatography.Title product is to obtain with oily matter form.
IR：ν：C＝O：1674-1745cm -1
m/z(C 12H 20N 2O 5)：272.1(M+)；295.121(M+Na) +；567.253(2M+Na) +
step B: 4-(tert-butoxycarbonyl)-1-formyl radical-2-piperazinecarboxylic acid lithium
In the 515mL dioxane solution of the compound (103mmol) obtaining to 28g steps A, add the 100mL H of 4.8g LiOH (113mmol) 2o solution.Entirety is stirred 4 hours in envrionment temperature.Subsequently reaction mixture is concentrated into dry, then with ethyl acetate coevaporation for several times.Title product is to obtain with solid form, and is directly used in crystallisation step below.
13c-NMR: δ (500MHz; Dmso-d6; 300 ° of K): 46 (s, C piperazines); 42-38 (m, C piperazine); 58-53 (s, C piperazine); 28.5 (s, C tbu).
IR：ν：C＝O：1650cm -1；2800cm -1
step C: 3,4-pyrrolin is [1,2-a] pyrazine-2 also, 8 (1H)-dioctyl phthalate 2-tert-butyl ester 8-methyl esters
In the 800mL ethylene dichloride suspension of the compound (103mmol) obtaining to 29g step B, add successively 24g toluene sulfonyl chloride (124mmol), 12.6mL2-chloracrylic acid methyl esters (124mmol), then add 35mL triethylamine (247mmol).Entirety is stirred 2 hours under refluxing.After cooling, reaction mixture is diluted by ethyl acetate, and by organic phase with saturated NaCl solution washing until neutrality.Through MgSO 4dry, filter and be concentrated into dry after, title product is separated to (sherwood oil/AcOEt gradient: 0-20%) by silica gel chromatography, be solid form.
H-NMR: δ (400MHz; Dmso-d6; 300 ° of K): 6.8-6.43 (m, 2H, H pyrroles); 4.75-3.75 (m, 6H, H piperazine)); 3.73 (s, 3H, H COOCH3); 1.48 (s, 9H, H tbu).
IR: ν: C=O (ester of conjugation): 1712cm -1; C=O (carbamate): 1677cm -1
step D: 6-[2-(tert-butoxycarbonyl)-8-(methoxycarbonyl)-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine-6-yl also]-1,3-benzo dioxole-5-formic acid
The method is as the scheme of describing in the step C of preparation example 1 and D.
preparation example 18:6-[7-(methoxycarbonyl)-2,3-dihydro-1H-pyrrolizine-5-yl]-1,3-benzo dioxole-5-formic acid
The scheme that the method is described as preparation example 1, with proline(Pro) replacement steps A Pipecolic Acid used.
preparation example 19:the chloro-2-[7-of 4-(methoxycarbonyl)-2,3-dihydro-1H-pyrrolizine-5-yl] phenylformic acid
The scheme that the method is described as preparation example 1, replaces steps A Pipecolic Acid used with proline(Pro), and step C 6-used is bromo-1, and 3-benzo dioxole-5-formaldehyde replaces with the bromo-4-chlorobenzaldehyde of 2-.
preparation example 20:the chloro-2-[8-of 4-(methoxycarbonyl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-6-yl] phenylformic acid
The scheme that the method is described as preparation example 1, replaces Pipecolic Acid with 3-morpholine formic acid, and step C 6-used is bromo-1, and 3-benzo dioxole-5-formaldehyde replaces with the bromo-4-chlorobenzaldehyde of 2-.
preparation example 21:6-[8-(methoxycarbonyl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-6-yl]-1,3-benzo dioxole-5-formic acid
The scheme that the method is described as preparation example 1, with 3-morpholine formic acid replacement Pipecolic Acid.
preparation example 22:the chloro-2-[1-of 4-(methoxycarbonyl)-6,7,8,9-tetrahydrochysene-5H-pyrrolo-[1,2-a] azepine -3-yl] phenylformic acid
The scheme that the method is described as preparation example 1, replaces Pipecolic Acid with 2-azepan formic acid, and step C 6-used is bromo-1, and 3-benzo dioxole-5-formaldehyde replaces with the bromo-4-chlorobenzaldehyde of 2-.
preparation example 23:6-[1-(methoxycarbonyl)-6,7,8,9-tetrahydrochysene-5H-pyrrolo-[1,2-a] azepine -3-yl]-1,3-benzo dioxole-5-formic acid
The scheme that the method is described as preparation example 1, with 2-azepan formic acid replacement Pipecolic Acid.
preparation example 24: the chloro-2-[3-of 4-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-1-indolizine base] phenylformic acid
steps A:1-(4-brombutyl)-1H-pyrroles-2-methyl-formiate
In 0 DEG C of anhydrous THF suspension of the 400mL to 6.7g (241.7mmol) NaH (60%), add 20g (161.13mmol) 1H-pyrroles-2-methyl-formiate (referring to Tetrahedron2008,64,7745).Subsequently entirety is stirred 1 hour in envrionment temperature.Then, add 95mL1,4-dibromobutane.After adding, reaction mixture is heated 12 hours under refluxing.Filter the throw out obtaining, then wash with THF.Subsequently filtrate is concentrated into dry.Then by compound by silica gel chromatography separate (cyclohexane/ethyl acetate gradient: 0 to 20%), oily matter form.
Elemental microanalysis:
IR：ν：-C＝O：1700cm -1；ν：C-O-C：1238cm -1
step B: 5,6,7,8-tetrahydrochysene-3-indolizine methyl-formiate
The 700mL acetonitrile solution of the derivative of the bromination that 8g (30.8mmol) steps A is obtained refluxes.Add wherein 25g Diisopropyl azodicarboxylate (151mmol) and 30g Bu 3the 500mL toluene solution of SnH (100mmol) mixture.By integral back-flow 120 hours.Subsequently reaction mixture is concentrated into dry.Then compound being separated to (cyclohexane/ethyl acetate gradient 5 to 10%) by silica gel chromatography, is oily matter form.
1h-NMR: δ (400MHz; CDCl 3; 300 ° of K): 6.90 (d, 1H, H pyrroles); 5.85 (d, 1H, H pyrroles); 4.30 (t, 2H, CH 2indolizine); 3.80 (s3H, Me); 2.80 (t, 2H, CH 2indolizine); 1.95 (m, 2H, CH 2indolizine); 1.80 (m, 2H, CH 2indolizine)
IR：ν：-C＝O：1695cm -1
step C: the chloro-2-[3-of 4-(methoxycarbonyl)-5,6,7,8-tetrahydrochysene-1-indolizine base] phenylformic acid
The method is as the scheme of describing in the step C of preparation example 1 and D.
preparation example 25: 2-[1-(methoxycarbonyl)-5,6,7,8-indolizine-3-yl]-4-tolyl acid
The method is as the method for preparation example 1, replaces step C 6-used bromo-1 with the bromo-4-tolyl aldehyde of 2-, 3-benzo dioxole-5-formaldehyde.
preparation example 26:the fluoro-2-[8-of 4-(methoxycarbonyl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-6-yl] phenylformic acid
The scheme that the method is described as preparation example 1, replaces Pipecolic Acid with 3-morpholine formic acid, and bromo-1 with the bromo-4-fluorobenzaldehyde replacement of 2-step C 6-used, 3-benzo dioxole-5-formaldehyde.
preparation example 27:the fluoro-2-[1 ' of 4--(methoxycarbonyl)-5 ', 6 '-dihydro-8 ' H-spiral shell [DOX-2,7 '-indolizine]-3 '-yl] phenylformic acid
steps A: 8-formyl radical-Isosorbide-5-Nitrae-dioxa-8-azaspiro [4.5] decane-7-methyl-formiate
By 24g1,4-dioxa-8-azaspiro [4.5] decane-9-methyl-formiate (111mmol) is dissolved in 80mL ethyl acetate and 80mL methylene dichloride.Add 26g (4-nitrophenyl) formate (155mmol), entirety is stirred 1 hour in envrionment temperature.Reaction mixture is evaporated to dry, and is dissolved in ethyl acetate.Subsequently organic phase is used successively to 1N NaOH solution, water washing, then used saturated NH 4cl solution washing is until reach neutral pH.With after through dried over mgso, filter and be concentrated into dry.Thus obtained oily matter is passed through to purification by flash chromatography (heptane/ethyl acetate gradient).Title product is to obtain with oily matter form.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K): 8.15 (s, 1H, CHO); 5.0-4.75 (m, 1H, uncle H); 4.3-3.7 (m, 5H, 4H ethylidene dioxy base+1H aliphatics piperidines); 3.70 (s, 3H, Me); 3.4-2.9 (2m, 1H, H aliphatics piperidines); 2.3-1.75 (m, 2H, H aliphatics piperidines); 1.7-1.5 (m, 2H, H aliphatics piperidines)
step B: 8-formyl radical-Isosorbide-5-Nitrae-dioxa-8-azaspiro [4.5] decane-7-formic acid
The compound (62.7mmol) that 15.25g steps A is obtained is dissolved in 160mL bis- in alkane.Drip 125mL1M KOH solution, and entirety is stirred 1 hour in envrionment temperature.Add subsequently 125mL1M HCl, and use dichloromethane extraction compound.By organic phase through MgSO 4dry, filter and be concentrated into dry.Title product is to obtain with powder type.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K) 13.5-12 (m, 1H, OH); 8.1+8.0 (2s, 1H, CHO); 4.9+4.6 (2m, 1H, uncle H); 4.0-3.8 (m, 4H, ethylidene dioxy base); 4.2+3.7 (2ms, 1H, H aliphatics piperidines); 3.4+2.9 (2m, 1H, H aliphatics piperidines); 2.4-1.5 (m, 4H, H aliphatics piperidines)
IR: ν: OH:3500-2000cm -1;-C=O (acid+aldehyde): 1731+1655cm -1
step C: 5 ', 6 '-dihydro-8 ' H-spiral shell [DOX-2,7 '-indolizine]-1 '-methyl-formiate
In the sour 380mL dichloromethane solution obtaining to 13.5g (62.7mmol) step B, add successively 39.5mL (238.4mmol) triethylamine, then add 12.5g (65.6mmol) Tosyl chloride and 23.7mL (238.4mmol) chloracrylic acid methyl esters by spoon.Entirety is stirred 18 hours at 80 DEG C.With after through diatomite filtration reaction mixture.Filtrate is used saturated NaHCO 3solution washing, then uses saturated NH 4cl solution washing.By organic phase through MgSO 4dry, filter and be concentrated into dry.Thus obtained oily matter is passed through to purification by flash chromatography (heptane/ethyl acetate gradient).Product is to obtain with solid form.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K) 6.70 (d, 1H, pyrroles); 6.40 (d, 1H, pyrroles); 4.05 (t, 2H, H aliphatics, piperidines); 4.00 (m, 4H, ethylidene dioxy bases); 3.70 (s, 3H, methyl); 3.15 (s, 2H, H aliphatics piperidines); 2.05 (t, 2H, H aliphatics piperidines)
IR: ν :-C=O (ester): 1689cm -1
step D: 3 '-(the fluoro-2-formyl radical of 5-phenyl)-5 ', 6 '-dihydro-8 ' H-spiral shell [DOX-2,7 '-indolizine]-1 '-methyl-formiate
The method is as the method for the step C of preparation example 1, replaces 6-bromo-1 with the bromo-4-fluorobenzaldehyde of 2-, 3-benzo dioxole-5-formaldehyde.
step e: the fluoro-2-[1 ' of 4--(methoxycarbonyl)-5 ', 6 '-dihydro-8 ' H-spiral shell [DOX-2,7 '-indolizine]-3 '-yl] phenylformic acid
The method is as the method for the step D of preparation example 1.
preparation example 28:the fluoro-2-[(2R of 4-)-2-hydroxyl-7-(methoxycarbonyl)-2,3-dihydro-1H-pyrrolizine-5-yl] phenylformic acid
steps A: (the 4R)-4-{[tertiary butyl (dimethyl) silyl] oxygen base }-L-PROLINE methyl esters
Protecting the alcohol functional group of (4R)-CHP methyl esters by t-butyldimethylsilyl is to carry out according to the scheme of describing in document WO2012040242.
step B:(4R)-4-{[the tertiary butyl (dimethyl) silyl] oxygen base }-1-formyl radical-L-PROLINE methyl esters
The compound of 13.7g (52.8mmol) steps A is dissolved in 100mL acetonitrile.Add wherein (4-nitrophenyl) formate and 39mL (238mmol) diisopropyl ethyl amine of 13.2g (79.3mmol).Entirety is stirred 6 hours in envrionment temperature.Reaction mixture is evaporated to dry doubling and is dissolved in ethyl acetate.Subsequently organic phase is used successively to 1N NaOH solution, water washing, then used saturated NH 4cl solution washing is until neutrality.With after through dried over mgso, filter and be concentrated into dry.By thus obtained oily matter by purification by flash chromatography (gradient: methylene dichloride/containing the methyl alcohol of ammoniacal liquor).Title product is to obtain with oily matter form.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K): 8.15 and 8.12 (s, 1H, formyl radicals); 4.62 and 4.25 (t, 1H, H α esters); 4.40 (m, 1H, SiOCH); 3.65 and 3.6 (s, 3H, OMe); 3.5 and 3.3 (m, 2H, 2H proline(Pro)); 2.12 and 1.95 (m, 2H, 2H proline(Pro)); 0.8 (s, 9H, Si tbu); 0.05 (s, 6H, SiMe 2).
IR: ν: C=O ester: 1749cm -1; C=O formyl radical: 1659cm -1
step C:(2S, 4R)-4-{[tertiary butyl (dimethyl) silyl] oxygen base }-1-carbonyl pyrrolidine-2-lithium formate
By the compound (26.2g of step B; 91.1mmol) be dissolved in 450mL dioxane.Add lithium hydroxide (4.2g; Water (90mL) solution 100mmol).Entirety is stirred 7 hours in envrionment temperature.Reaction mixture is evaporated to dry doubling and is directly used in next step.
step D:(2R)-2-{[the tertiary butyl (dimethyl) silyl] oxygen base }-2,3-dihydro-1H-pyrrolizine-7-methyl-formiate
In the 640mL dichloroethane solution of the lithium formate obtaining to 22.4g (80.2mmol) step D, add successively 27mL (192mmol) triethylamine, then add 18g (96mmol) Tosyl chloride and 9.7mL (96.2mmol) chloracrylic acid methyl esters in batches.Reaction mixture is heated 18 hours under refluxing, then cooling, and be diluted in ethyl acetate.Organic phase is washed with water, then use salt water washing, afterwards through MgSO 4dry.After filtration and enriched mixture, the oily matter obtaining is passed through to purification by flash chromatography (gradient: heptane/ethyl acetate).Title product is to obtain with oily matter form.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K): 6.7 (d, 1H, H pyrroles); 6.4 (d, 1H, H pyrroles); 5.0 (m, 1H, SiOCH); 4.2-3.75 (ABx, 2H, piperazine in 2H pyrrolin); 3.3+2.8 (ABx, 2H, piperazine in 2H pyrrolin); 3.70 (s, 3H, CO 2cH 3); 0.9 (s, 9H, tbu); 0.10 (ABx, 6H, SiMe 2)
IR: ν :-C=O (ester): 1701cm -1; SiCH 3: 1249cm -1; Si-O:1118-1090cm -1; Si-C:835-777cm -1
step e: (the 2R)-2-{[tertiary butyl (dimethyl) silyl] oxygen base }-5-(the fluoro-2-formyl radical of 5-phenyl)-2,3-dihydro-1H-pyrrolizine-7-methyl-formiate
The method is as the method for the step C of preparation example 1, replaces 6-bromo-1 with the bromo-4-fluorobenzaldehyde of 2-, 3-benzo dioxole-5-formaldehyde.
step F: 2-[(2R)-2-{[the tertiary butyl (dimethyl) silyl] oxygen base }-7-(methoxycarbonyl)-2,3-dihydro-1H-pyrrolizine-5-yl]-4-fluorobenzoic acid
The method is as the method for the step D of preparation example 1.
preparation example 29:the fluoro-2-[(2S of 4-)-2-hydroxyl-7-(methoxycarbonyl)-2,3-dihydro-1H-pyrrolizine-5-yl] phenylformic acid
The method is as the method for preparation example 28, with (4S)-CHP methyl esters replacement (4R)-CHP methyl esters.
preparation example 30:the fluoro-2-[7-hydroxyl-1-of 4-(methoxycarbonyl)-5,6,7,8-indolizine-3-yl] phenylformic acid
The method is as the method for preparation example 27, and bromo-1 with 6-, 3-benzo dioxole-5-formaldehyde replaces the bromo-4-fluorobenzaldehyde of 2-.
preparation example 31:6-[8-(methoxycarbonyl) pyrrolo-[1,2-a] pyrazine-6-yl]-1,3-benzo dioxole-5-formic acid
steps A: pyrrolo-[1,2-a] pyrazine-8-methyl-formiate
In 263mL anhydrous propanone (4mL/mmol) solution of 10g (65.7mmol) pyrazine-2-guanidine-acetic acid methyl esters, add successively 5.7g lithiumbromide (65.7mmol), 22.1g sodium bicarbonate (263mmol), then add 9.4mL monochloroacetaldehyde (50% aqueous solution) (72.6mmol).Subsequently by entirety heated overnight under refluxing.Subsequently reaction mixture is concentrated into dryly, then is dissolved in ethyl acetate.Organic phase is washed with saturated nacl aqueous solution, through dried over mgso, filter and be concentrated into dry.Obtain oily matter, passed through silica gel chromatography purifying (CH 2cl 2/ ethyl acetate gradient).After concentrated, title product is to obtain with solid form.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K): 9.36 (m, 1H, H pyrazines); (8.50 dd, 1H, H pyrazine)); 7.8 (m, 2H, 1H pyrazine, 1H pyrroles); 7.31 (m, 1H, H pyrroles) .3.88 (s, 3H, OCH 3)
IR: ν :-C=O (ester of conjugation): 1686cm -1
step B: 6-[8-(methoxycarbonyl) pyrrolo-[1,2-a] pyrazine-6-yl]-1,3-benzo dioxole-5-formic acid
The method is as the method for the step C of preparation example 1 and D.
preparation example 32:the fluoro-2-[1-of 4-(methoxycarbonyl)-3-indolizine base] phenylformic acid
1-indolizine methyl-formiate is to form according to the method for describing in the steps A of preparation example 13 and B.Title product obtains according to the scheme described in the step C of preparation example 1 and D subsequently, replaces step C 6-used bromo-1 with the bromo-4-fluorobenzaldehyde of 2-, 3-benzo dioxole-5-formaldehyde.
preparation example 1 ': (3S)-3-(4-morpholinyl methyl)-1,2,3,4-tetrahydroisoquinoline
steps A: (3S)-3-(4-morpholinyl carbonyl)-3,4-dihydro-2 (1H)-isoquinoline 99.9 benzyl formate
To 5g (3S)-2-[(benzyl oxygen base) carbonyl]-1,2,3, in the 160mL dichloromethane solution of 4-tetrahydrochysene-3-isoquinoline 99.9 formic acid (16mmol), add 1.5mL morpholine (17.6mmol), then add 9mLN, N, N-triethylamine (64mmol), 3.3g1-ethyl-3-(3 '-dimethylaminopropyl)-carbodiimide (EDC) (19.2mmol) and 2.6g hydroxybenzotriazole (HOBT) (19.2mmol).Reaction mixture is stirred and spent the night in envrionment temperature, then pour in ammonium chloride solution and be extracted with ethyl acetate.By organic phase with after through dried over mgso, then filter and be evaporated to dry.Then thus obtained crude product is passed through to silica gel chromatography purifying (methylene chloride/methanol gradient).Product is to obtain with foam form.
1h-NMR: δ (400MHz; Dmso-d6; 353 ° of K): 7.30 (m, 5H benzyls); 7.15 (m, 4H aromatics); 5.2-5.0 (m, 3H, 2H benzyl, 1H dihydro-isoquinoline); (4.75-4.5 2d, 2H dihydro-isoquinoline); (3.55-3.3 m, 8H morpholine); (3.15-2.9 2dd, 2H dihydro-isoquinoline)
IR：ν：>C＝O：1694；1650cm -1
step B: (3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinoline 99.9 benzyl formate
In the 278mL tetrahydrofuran solution of the product (13.9mmol) obtaining to 5.3g steps A in envrionment temperature, add 14mL BH 3me 2s (27.8mmol).Entirety is heated 4 hours at 80 DEG C.Got back to envrionment temperature, then added 7mL (14mmol) BH 3me 2s.Again reaction mixture is heated 2 hours at 80 DEG C.Tetrahydrofuran (THF) is removed in evaporation subsequently, then slowly adds methyl alcohol, then adds 5.6mL5N hydrochloric acid (27.8mmol).Mixture is stirred and spent the night in envrionment temperature, then stir 1 hour at 80 DEG C.In reaction mixture, add saturated NaHCO at 0 DEG C subsequently 3solution, until reach pH8, is then extracted with ethyl acetate.By organic phase with after through dried over mgso, then filter and be evaporated to dry.Title product is to obtain with oily matter form.
1h-NMR: δ (400MHz; Dmso-d6; 353 ° of K): 7.43-7.30 (unresolved peak, 5H benzyl); 7.19 (m, 4H aromatics); (5.16 m, 2H, 2H benzyl); (4.79-4.29 d, 2H dihydro-isoquinoline); (4.58 m, 1H dihydro-isoquinoline); (3.50 m, 4H morpholine); (3.02-2.80 dd, 2H dihydro-isoquinoline); 2.42-2.28 (unresolved peak, 5H, 4H morpholine, 1H morpholine); (2.15 dd, 1H morpholine)
IR：ν：>CH：2810cm -1；ν：>C＝O：1694cm -1；ν：>C-O-C<：1114cm -1；ν：>CH-Ar：751；697cm -1
step C: (3S)-3-(4-morpholinyl methyl)-1,2,3,4-tetrahydroisoquinoline
In the 67mL ethanolic soln of 4.9g step B compound (13.4mmol), add 0.980g bis-palladium hydroxides (20% quality) in envrionment temperature.Reaction mixture is placed 4 hours in envrionment temperature under 1.2 bar hydrogen.Passed through subsequently Whatman strainer, then by ethanol drip washing several for palladium.Filtrate is evaporated to dry.Title product is to obtain with oily matter form.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K): 7.12-7.0 (unresolved peak, 4H aromatics); 3.92 (s, 2H tetrahydroisoquinolines); 3.60 (t, 4H morpholines); 2.98 (m, 1H tetrahydroisoquinolines); 2.68 (dd, 1H tetrahydroisoquinolines); 2.5-2.3 (unresolved peak, 8H, 1H tetrahydroisoquinoline, 6H morpholine, 1H NH)
IR：ν：>NH：3322cm -1；ν：>C-O-C<：1115cm -1；ν：>CH-Ar：742cm -1
preparation example 2 ': (3R)-3-(4-morpholinyl methyl)-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with (3R)-2-[(benzyl oxygen base) carbonyl]-1,2,3,4-tetrahydrochysene-3-isoquinoline 99.9 formic acid replaces steps A (3S)-2-[(benzyl oxygen base used) carbonyl]-1,2,3,4-tetrahydrochysene-3-isoquinoline 99.9 formic acid.
preparation example 3 ':(3S)-3-[(4-methyl isophthalic acid-piperazinyl) methyl]-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with 1-methyl-piperazine replacement steps A morpholine used.
preparation example 4 ':(3S)-3-(Isosorbide-5-Nitrae-oxa-azepan-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with Isosorbide-5-Nitrae-oxa-azepan replacement steps A morpholine used.
preparation example 5 ':(3S)-3-{[(3R)-3-methylmorpholine base] methyl }-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with (3R)-3-methylmorpholine replacement steps A morpholine used.
preparation example 6 ':(3S)-3-{[(3S)-3-methylmorpholine base] methyl }-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with (3S)-3-methylmorpholine replacement steps A morpholine used.
preparation example 7 ':(3S)-3-{[(3S, 5S)-3,5-dimethylated morpholinyl] methyl }-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', and with (3S, 5S)-3,5-thebaine replaces steps A morpholine used.
preparation example 8 ':n, N-dimethyl [(3S)-1,2,3,4-tetrahydrochysene-3-isoquinolyl] methylamine
The method is as the method for preparation example 1 ', and with N, N-dimethyl amine replaces steps A morpholine used.
preparation example 9 ':(3S)-3-{[4-(2-methoxy ethyl) piperazine-1-yl] methyl }-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with 1-(2-methoxy ethyl) piperazine replacement steps A morpholine used.
preparation example 10 ':1-methyl-4-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-ylmethyl] piperazine-2-ketone
The method is as the method for preparation example 1 ', with 1-methylpiperazine-2-ketone replacement steps A morpholine used.
preparation example 11 ':2-methoxyl group-N-methyl-N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-ylmethyl] ethamine
The method is as the method for preparation example 1 ', with 2-methoxyl group-N-methyl ethyl-amine replacement steps A morpholine used.
preparation example 12 ':n-ethyl-2-methoxyl group-N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-ylmethyl] ethamine
The method is as the method for preparation example 1 ', with N-ethyl-2-methoxyethyl amine replacement steps A morpholine used.
preparation example 13 ':(3S)-3-{[4-(methyl sulphonyl) piperazine-1-yl] methyl }-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with 1-(methyl sulphonyl) piperazine replacement steps A morpholine used.
preparation example 14 ':(3S)-3-{[4-(2,2,2-trifluoroethyl) piperazine-1-yl] methyl }-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with 1-(2,2,2-trifluoroethyl) piperazine replacement steps A morpholine used.
preparation example 15 ':(3S)-3-[(1,1-titanium dioxide (oxido) thiomorpholine-4-yl) methyl]-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', and with thiomorpholine 1,1-dioxide replaces steps A morpholine used.
preparation example 16 ':(3S)-3-[(3-methoxyl group pyrrolidin-1-yl) methyl]-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with 3-methoxyl group tetramethyleneimine replacement steps A morpholine used.
preparation example 17 ':(3S)-3-[(3,3-difluoro pyrrolidin-1-yl) methyl]-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with 3,3-, bis-fluoropyrrolidines replacement steps A morpholine used.
preparation example 18 ':(3S)-3-[(3-methoxyl group azetidine-1-yl) methyl]-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with 3-methoxyl group azetidine replacement steps A morpholine used.
preparation example 19 ':(3S)-3-[(3-fluorine azetidine-1-yl) methyl]-1,2,3,4-tetrahydroisoquinoline
The method is as the method for preparation example 1 ', with 3-fluorine azetidine replacement steps A morpholine used.
preparation example 1 ": the 4-{[tertiary butyl (dimethyl) silyl] oxygen base }-N-phenylaniline
In the 200mL acetonitrile solution of 12g4-anilino phenol (64.7mmol), add 6.7g imidazoles (97.05mmol) and the 11.7g tertiary butyl (chlorine) dimethylsilane (77.64mmol) in envrionment temperature.Entirety is stirred 4 hours at 70 DEG C.Then reaction mixture is poured into water and extracts with ether.By organic phase with after through dried over mgso and filtration and be evaporated to dry.Then thus obtained crude product is passed through to silica gel chromatography purifying (sherwood oil/dichloromethane gradient).Title product is to obtain with powder type.
1h-NMR: δ (400MHz; Dmso-d6; 300 ° of K): 7.84 (s, 1H NH); 7.17 (t, 2H aniline); 6.98 (d, 2H phenoxy groups); 6.94 (d, 2H aniline); 6.76 (d, 2H phenoxy groups); 6.72 (t, 1H aniline); 0.95 (s, the 9H tertiary butyl); 0.15 (s, 6H dimethyl)
IR：ν：>NH：3403cm -1；>Ar：1597cm -1
Amine NHR 3r 4(wherein R 3and R 4represent independently of one another aryl or heteroaryl) be according to document (people such as Surry D.S, Chemical Science, 2011,2,27-50, the people such as Charles M.D., Organic Letters, 2005,7,3965-3968) in the currently known methods described prepare.Preparation example 1 " in the protective reaction of hydroxy functional group of the 4-anilino phenol described can be applied to the different secondary amine NHR with one or more hydroxy functional groups 3r 4(as hereinbefore defined), in the time that they can be commercially available.Or the secondary amine with at least one hydroxyl substituent can be directly synthetic with protection form, started by the reagent of the hydroxy functional group of protecting in advance.In protecting group, particularly preferably tertiary butyl silyl oxygen base and benzyl oxygen base.
At the amine NHR with hydroxyl substituent for the synthesis of the compounds of this invention 3r 4in can mention: 4-(4-toluino) phenol, 4-(4-chloroanilino) phenol, 4-(the fluoro-4-toluidine of 3-) phenol, 4-[4-(trifluoromethoxy) anilino] phenol, 4-[4-hydroxybenzene amido] phenol, 4-[(1-Methyl-1H-indole-6-yl) and amino] phenyl } methyl alcohol, 4-(2, 3-dihydro-1H-indoles-6-base amino) phenol, 4-[(1-methyl-2, 3-dihydro-1H-indoles-6-yl) amino] phenol, 4-[(1-Methyl-1H-indole-6-yl) amino] phenol, 4-[(1-Methyl-1H-indole-6-yl) amino] hexalin, 4-[(1-methyl isophthalic acid, 2, 3, 4-tetrahydrochysene-6-quinolyl) amino] phenol, 4-[(4-methyl-3, 4-dihydro-2H-1, 4-benzo piperazine-7-yl) amino] phenol, 4-[4-(diethylamino) anilino] phenol, 4-(2,3-dihydro-1H-indenes-5-base amino) phenol, 4-[(1-methyl isophthalic acid H-indazole-5-yl) amino] phenol, 4-[(1 '-methyl isophthalic acid ', 2 '-dihydroxyl spiral shell [cyclopropane-1,3 '-indoles]-5 '-yl) amino] phenol, 4-[(1,3,3-dimethyl-2,3-dihydro-1H-indoles-5-yl) amino] phenol, 4-[4-methoxyl group-3-(trifluoromethyl) anilino] phenol, 4-[4-(methyl sulfanyl)-3-(trifluoromethyl) anilino] phenol, the fluoro-4-[(1-Methyl-1H-indole-5-of 2-yl) amino] phenol, 4-[(1-ethyl-1H-indoles-5-yl) amino] phenol, 4-[(1-ethyl-2,3-dihydro-1H-indoles-5-yl) amino] phenol, 4-[(1-sec.-propyl-2,3-dihydro-1H-indoles-5-yl) amino] phenol, 4-(butyl amino) phenol, 3-[(1-Methyl-1H-indole-5-yl) amino]-1-propyl alcohol, 4-[(1-Methyl-1H-indole-5-yl) amino]-n-butyl alcohol, the fluoro-4-aminomethyl phenyl of 4-[(3-) amino] phenol, the chloro-4-aminomethyl phenyl of 4-[(3-) amino] phenol, 4-[(4-fluorophenyl) amino] phenol, 4-[(1-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-5-yl) amino] phenol, 4-[(4-fluorophenyl) amino] phenol, 4-[(2-fluorophenyl) amino] phenol, 4-[(3-fluorophenyl) amino] phenol, 4-[(2,4-difluorophenyl) amino] phenol, 4-[(3,4-difluorophenyl) amino] phenol, 3-[(4-hydroxy phenyl) amino] benzonitrile, 4-[(3-p-methoxy-phenyl) amino] phenol, 4-[(3,5-difluorophenyl) amino] phenol, 4-[(3-aminomethyl phenyl) amino] phenol, 4-[(4-hydroxy phenyl) amino] benzonitrile, 4-[(3-chloro-phenyl-) amino] phenol, 4-(pyrimidine-2--amino) phenol, 4-[(cyclobutylmethyl) amino] phenol, 2-[(4-hydroxy phenyl) amino] benzonitrile, 4-{[(1-methyl isophthalic acid H-pyrazoles-4-yl) methyl] amino } phenol, 4-[(cyclopropyl methyl) amino] phenol, 4-{[(1-methyl isophthalic acid H-pyrazole-3-yl) methyl] amino } phenol, 4-(fourth-2-alkynes-1-base amino) phenol, 4-(pyrazine-2-base amino) phenol, 4-(pyridine-2-base amino) phenol, 4-(pyridazine-3-base amino) phenol, 4-(pyrimidine-5-base amino) phenol, 4-(pyridin-3-yl amino) phenol, 4-[(3, the fluoro-4-p-methoxy-phenyl of 5-bis-) amino] phenol, 4-(pyridin-4-yl amino) phenol, the fluoro-4-p-methoxy-phenyl of 4-[(3-) amino] phenol, 2-(phenyl amino) pyrimidine-5-alcohol, 5-[(4-hydroxy phenyl) amino]-2-HOMOVERATRONITRILE, 4-{[3-(trifluoromethyl) phenyl] amino } phenol.
The hydroxy functional group of secondary amine listed above is by protecting in advance before the acid derivative of applicable protecting group defined formula (VII) compound in being coupled to as previous universal method.
embodiment 1:n-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
steps A: 3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methyl-formiate
In the 20mL dichloromethane solution of the compound of 2g preparation example 1, add 5.5mL N in envrionment temperature, N, the compound (6.96mmol) of N-triethylamine (6.96mmol), 2.12g preparation example 1 ', then adds 0.94g hydroxybenzotriazole (HOBT) and 1.34g1-ethyl-3-(3 '-dimethylaminopropyl)-carbodiimide (EDC) (6.96mmol).Reaction mixture is stirred and spent the night in envrionment temperature subsequently, be then poured in ammonium chloride solution and be extracted with ethyl acetate.By organic phase with after through dried over mgso, then filter and be evaporated to dry.Thus obtained crude product is passed through to silica gel chromatography purifying (heptane/AcOEt gradient).Title product is to obtain with oily matter form.
1h-NMR: δ (500MHz; Dmso-d6; 300 ° of K): 7.2-6.9 (m, 4H, H aromatics); 7.04-7.03-7.00 (m, 1H, H aromatics); 6.85 (m, 1H, H aromatics); 6.35-6.26-6.06 (m, 1H, H indolizine); (6.15-6.12 m, 2H, H m ethylidene dioxy base); 5.06-4.84 (m, 1H, H dihydro-isoquinoline); 4.86-4.17 (m, 2H, H dihydro-isoquinoline); (3.65-3.6-3.55 m, 3H, H methyl esters); 3.43-4.26 (m, 2H, H indolizine); 3.58-3.5 (m, 4H, H morpholine); (2.37-3.05 m, 4H, 2H dihydro-isoquinoline, 2H indolizine); 1.68-2.56 (m, 4H, H morpholine); 1.4-2.0 (m, 4H, H indolizine)
IR: ν: >C=O1695cm -1ester; ν: >C=O1625cm -1acid amides; ν: >C-O-C<1214-1176-1115cm -1; >CH-Ar772-744cm -1
step B:3-[6-[(3S)-3-(morpholino methyl)-3,4-dihydro-1H-isoquinoline 99.9-2-carbonyl]-1,3-benzo dioxole-5-yl]-5,6,7,8-tetrahydrochysene-1-indolizine lithium formate
In the 24mL dioxane solution of the compound (8.26mmol) of 4.6g steps A, add lithium hydroxide solution (675mg, 16.1mmol).Entirety is placed 2.5 hours in 100 DEG C of 140W microwave ovens.By reaction mixture subsequent filtration and dry.Be there is to P in thus obtained solid 2o 540 DEG C of hot cabinets in dry.
1h-NMR: δ (400MHz; Dmso-d6; 353 ° of K): 6.7-7.15 (unresolved peak, 6H, H aromatics); 6.21 (s, 1H, H aromatics); 6.03 (s, 2H, H methylene radical dioxy bases); 4.0-5.0 (unresolved peak, 3H dihydro-isoquinoline); 3.4-3.6 (unresolved peak, 3H indolizine, 3H morpholine); 2.5-3.1 (unresolved peak, 4H, 2H indolizine, 2H morpholine); 1.5-2.4 (unresolved peak, 10H morpholine)
IR: ν: >C=O1567 broad peak cm -1acetic ester; ν: 1236cm -1
step C:n-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
In the 47mL dichloromethane solution of 0 DEG C of compound to 2.6g step B (4.73mmol), drip 1.2mL oxalyl chloride.Reaction mixture is stirred 11 hours in envrionment temperature, then with methylene dichloride coevaporation several.Thus obtained product is suspended in 37mL methylene dichloride, then joins the 2.1g preparation example 1 that has 0.6mL pyridine (7.1mmol) " in the 10mL dichloromethane solution of compound (7.1mmol) that obtains.Entirety is stirred and spent the night in envrionment temperature.Concentrated reaction mixture and by silica gel chromatography purifying (methylene chloride/methanol gradient).Title product is to obtain with foam form.
1h-NMR: δ (500MHz; Dmso-d6; 300 ° of K): 6.9-7.3 (9H aromatics); 6.88 (2H aromatics); (6.72-6.87 2H aromatics); (6.64 2H aromatics); (6.13 2H methylene radical dioxy base); (5.05-4.74 1H dihydro-isoquinoline); (4.25-4.13 2H dihydro-isoquinoline); (3.44-3.7 4H morpholine); (3.62-3.52 2H indolizine); 3.0-2.6 (4H, 2H indolizine, 2H dihydro-isoquinoline); (2.54-1.94 6H morpholine); (1.91-1.53 4H indolizine); 0.92 (the 9H tertiary butyl); 0.17 (6H dimethyl)
IR：ν：>C＝O：1632cm -1；ν：>C-O-C<：1237cm -1；ν：-Si-O-C-：1035cm -1；-Si-C-：910cm -1；>CH-Ar：806cm -1
step D:n-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
In the 4mL methanol solution of the compound (2.3mmol) obtaining to 1.9g step C, add 0.646g (11.5mmol) to be dissolved in the potassium hydroxide in 8mL methyl alcohol.Entirety is stirred 30 minutes in envrionment temperature.Reaction mixture is diluted in methylene dichloride subsequently, and uses successively 1N HCl solution, saturated NaHCO 3solution and saturated NaCl solution washing, until reach neutral pH.By organic phase with after through dried over mgso, filter and evaporation.By thus obtained crude product purifying (methylene chloride/methanol gradient) on silica gel.Solid is dissolved in methylene dichloride subsequently, and adds the ethereal solution of 2mL1N hydrogenchloride.Entirety is stirred 1 hour, be then evaporated to dry.By in water-soluble thus obtained hydrochloride/acetonitrile mixture until completely dissolve, then by its freeze-drying.
Elemental microanalysis:
Rotatory power: (α) d 20=+50.8 ° (c=9mg/mL, MeOH)
embodiment 2:n-(4-hydroxy phenyl)-N-(4-aminomethyl phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, with the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(4-aminomethyl phenyl) aniline replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 3:n-(4-chloro-phenyl-)-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, with the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(4-chloro-phenyl-) aniline replaces step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+80.9 ° (c=2.5mg/mL, MeOH)
embodiment 4:n-(the fluoro-4-aminomethyl phenyl of 3-)-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, with the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(the fluoro-4-aminomethyl phenyl of 3-) aniline replaces step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 44h 43fN 4o 6
[M+H] +calculated value: 743.3245
[M+H] +measured value: 743.3250
Rotatory power: (α) d 20=+40.7 ° (c=2.5mg/mL, MeOH)
embodiment 5:n-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-[4-(trifluoromethoxy) phenyl]-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, with the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(4-Trifluoromethoxyphen-l) aniline replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 6:n, N-bis-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, with the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) aniline replaces step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+50.8 ° (c=6mg/mL, MeOH)
embodiment 7:n-[4-(hydroxymethyl) phenyl]-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, with N-[4-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) phenyl]-1-Methyl-1H-indole-5-amine replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 8:n-(2,3-dihydro-1H-indoles-5-yl)-N-[4-(hydroxyl) phenyl]-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide, two (hydrochlorides)
The method is as the method for embodiment 1, replaces step C preparation example 1 used with N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-5-indoline amine " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+40.9 ° (c=3.5mg/mL, MeOH)
embodiment 9:n-[4-(hydroxyl) phenyl]-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replaces step C preparation example 1 used with N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl-5-indoline amine " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 46h 47n 5o 6
[M+H] +calculated value: 766.3605
[M+H] +measured value: 766.3601
embodiment 10:n-[4-(hydroxyl) phenyl]-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replaces step C preparation example 1 used with N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine " compound.
Elemental microanalysis: (theoretical value 1.1HCl)
Rotatory power: (α) d 20=+37.6 ° (c=7mg/mL, MeOH)
embodiment 11:n-(4-hydroxy phenyl)-3-{6-[((3R)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 ' used with the compound of preparation example 2 '.
Elemental microanalysis:
Rotatory power: (α) d 20=-45.1 ° (c=9mg/mL, MeOH)
embodiment 12:n-(4-hydroxy-cyclohexyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replaces step C preparation example 1 used with N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } cyclohexyl)-1-Methyl-1H-indole-5-amine " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 46h 51n 5o 6
[M+H] +calculated value: 770.3918
[M+H] +measured value: 770.3928
embodiment 13:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-[(4-methyl isophthalic acid-piperazinyl) methyl]-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide, two (hydrochlorides)
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 ' used with the compound of preparation example 3 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+60.1 ° (c=6mg/mL, MeOH)
embodiment 14:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-(1,4-oxa-azepan-4-ylmethyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 ' used with the compound of preparation example 4 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 15:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-{[(3R)-3-methylmorpholine base] methyl }-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 ' used with the compound of preparation example 5 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 16:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-{[(3S)-3-methylmorpholine base] methyl }-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 ' used with the compound of preparation example 6 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 17:3-{6-[((3S)-3-{[(3S, 5S)-3,5-dimethylated morpholinyl] methyl }-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 ' used with the compound of preparation example 7 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace preparation example 1 " compound.
Elemental microanalysis:
embodiment 18:the bromo-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 2, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 45h 44 79brN 5o 4
[M+H] +calculated value: 798.2655
[M+H] +measured value: 798.2626
embodiment 19:the bromo-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 2, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl-5-indoline amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 45h 46 79brN 5o 4
[M+H] +calculated value: 800.2811
[M+H] +measured value: 800.2791
embodiment 20:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 used with the compound of preparation example 3.
Elemental microanalysis:
Rotatory power: (α) d 20=+53.7 ° (c=6mg/mL, MeOH)
embodiment 21:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(2,3-dihydro-1H-indoles-5-yl)-N-(4-hydroxy phenyl)-5,6,7,8-tetrahydrochysene-1-indolizine methane amide, two (hydrochlorides)
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-5-indoline amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 44h 44 35clN 5o 4
[M+H] +calculated value: 742.3160
[M+H] +measured value: 742.3120
embodiment 22:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+55.9 ° (c=7mg/mL, MeOH)
embodiment 23:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine methane amide, two (hydrochlorides)
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl-5-indoline amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+56.6 ° (c=6mg/mL, MeOH)
embodiment 24:the fluoro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 4, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+55.0 ° (c=5mg/mL, MeOH)
embodiment 25:the fluoro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation 1 used with the compound of preparation example 4.
Elemental microanalysis:
embodiment 26:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-6-quinolyl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-6-quinolyl amine replaces step C preparation example 1 used " compound.
Elemental microanalysis: (theoretical value 1.5HCl)
embodiment 27:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(4-methyl-3,4-dihydro-2H-1,4-benzo piperazine-7-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-4-methyl-3,4-dihydro-2H-1,4-benzo piperazine-7-amine replaces step C preparation example 1 used " compound.
Elemental microanalysis: (theoretical value 1.1HCl)
embodiment 28:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-[4-(diethylamino) phenyl]-N-(4-hydroxy phenyl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method, as the method for embodiment 1, replaces on the one hand the compound of steps A preparation example 1 used, and uses on the other hand N with the compound of preparation example 3 1-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-N 4, N 4-diethyl-Isosorbide-5-Nitrae-phenylenediamine replaces step C preparation example 1 used " compound.
Elemental microanalysis: (theoretical value 1.6HCl)
embodiment 29:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(2,3-dihydro-1H-indenes-5-yl)-N-(4-hydroxy phenyl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-5-indane amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 30:the chloro-2-[((3S of 3-{5-)-3-[(4-methyl isophthalic acid-piperazinyl) methyl]-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine methane amide, two (hydrochlorides)
The method is as the method for embodiment 1, on the one hand replace respectively the compound of steps A preparation example used 1 and 1 ' with the compound of preparation example 3 and 3 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine replacement step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 46h 47 35clN 6o 3
[M+H] +calculated value: 767.3476
[M+H] +measured value: 767.3476
embodiment 31:n-(4-hydroxy phenyl)-3-{8-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-3,4-dihydro-2H-1,5-benzo dioxa -7-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 used with the compound of preparation example 5.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 45h 46n 4o 6
[M+H] +calculated value: 739.3496
[M+H] +measured value: 739.3479
embodiment 32:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{8-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-3,4-dihydro-2H-1,5-benzo dioxa -7-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 5, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 33:n-(4-hydroxy phenyl)-3-{5-methoxyl group-2-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 6, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+42.1 ° (c=6mg/mL, MeOH)
embodiment 34:n-(4-hydroxy phenyl)-3-{7-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 used with the compound of preparation example 7.
Elemental microanalysis:
Rotatory power: (α) d 20=+34.5 ° (c=6mg/mL, MeOH)
embodiment 35:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{7-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 7, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound, should be understood that thus obtained product does not carry out the salt formation step under the ethereal solution of hydrogenchloride exists.
Elemental microanalysis:
Rotatory power: (α) d 20=+88.2 ° (c=7mg/mL, MeOH)
embodiment 36:3-{5-oxyethyl group-2-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 8, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 37:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{2,2-bis-deuteriums-6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 9, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 46h 43n 5o 6d 2
[M+H] +calculated value: 766.3573
[M+H] +measured value: 766.3533
Rotatory power: (α) d 20=+35.5 ° (c=3.5mg/mL, MeOH)
embodiment 38:n-(4-hydroxy phenyl)-3-{2,2-bis-deuteriums-6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
steps A:n-(4-hydroxy phenyl)-3-{2,2-bis-deuteriums-6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 used with the compound of preparation example 9, should be understood that salt formation step is only carried out in step B below under the ethereal solution of hydrogenchloride exists.
step B:n-(4-hydroxy phenyl)-3-{2,2-bis-deuteriums-6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The product that steps A is obtained is dissolved in methylene dichloride, and adds the ethereal solution of 2mL1N hydrogenchloride.Entirety is stirred 1 hour, be then evaporated to dry.By water-soluble thus obtained hydrochloride/acetonitrile mixture until completely dissolve, then by its freeze-drying.
Elemental microanalysis:
embodiment 39:n-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-3-{7-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 7, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-indazole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+42.6 ° (c=5mg/mL, MeOH)
embodiment 40:n-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-6-quinolyl)-3-{7-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 7, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-6-quinolyl amine replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 41:n-(4-hydroxy phenyl)-N-(4-methyl-3,4-dihydro-2H-1,4-benzo piperazine-7-yl)-3-{7-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 7, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-4-methyl-3,4-dihydro-2H-1,4-benzo piperazine-7-amine replaces step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 47h 49n 5o 7
[M+H] +calculated value: 796.3710
[M+H] +measured value: 796.3687
embodiment 42:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-indazole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 43:the chloro-2-[((3S of 1-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-5,6,7,8-tetrahydrochysene-3-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 24, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 44:the fluoro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 4, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-indazole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 45:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1 '-methyl isophthalic acid ', 2 '-dihydro spiral shell [cyclopropane-1,3 '-indoles]-5 '-yl)-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-(1 '-methyl isophthalic acid ', 2 '-dihydro spiral shell [cyclopropane-1,3 '-indoles]-5 '-yl) amine replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 46:the chloro-2-[((3S of 3-{5-)-3-(1,4-oxa-azepan-4-ylmethyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, on the one hand replace respectively the compound of steps A preparation example used 1 and 1 ' with the compound of preparation example 3 and 4 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine replacement step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+13.6 ° (c=4mg/mL, MeOH)
embodiment 47:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-[2-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-5-(trifluoromethyl) phenyl]-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 10, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 48:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-[2-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-5-(trifluoromethoxy) phenyl]-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 11, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 49:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1,3,3-trimethylammonium-2,3-dihydro-1H-indoles-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1,3,3-trimethylammonium-5-indoline amine replaces step C preparation example 1 used " compound, should be understood that thus obtained product does not carry out salt formation step under ether solution of hydrogen chloride exists.
Elemental microanalysis:
embodiment 50:n-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-3-{2,2-bis-deuteriums-6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 9, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-indazole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 51:n-(the fluoro-4-aminomethyl phenyl of 3-)-N-(4-hydroxy phenyl)-3-{2,2-bis-deuteriums-6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 9, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) the fluoro-4-monomethylaniline of-3-to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 52:the chloro-2-[((3S of 3-{5-)-3-[(dimethylamino) methyl]-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, on the one hand replace respectively the compound of preparation example 1 and 1 ' with the compound of preparation example 3 and 8 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine replacement step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 43h 42 35clN 5o 3
[M+H] +calculated value: 712.3054
[M+H] +measured value: 712.3060
Rotatory power: (α) d 20=+35.8 ° (c=6mg/mL, MeOH)
embodiment 53:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-[4-methoxyl group-3-(trifluoromethyl) phenyl]-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-4-methoxyl group-3-(trifluoromethyl) aniline to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 54:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-[4-(methyl sulfanyl)-3-(trifluoromethyl) phenyl]-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-4-(methyl sulfanyl)-3-(trifluoromethyl) aniline to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 55:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(the fluoro-4-hydroxy phenyl of 3-)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base }-3-fluorophenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 56:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{2-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 12, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 57:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-[(4-methyl isophthalic acid-piperazinyl) methyl]-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine methane amide two (hydrochloride)
The method is as the method for embodiment 1, on the one hand replace respectively the compound of steps A preparation example used 1 and 1 ' with the compound of preparation example 13 and 3 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine replacement step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+113.2 ° (c=6mg/mL, MeOH)
embodiment 58:n-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-1-indolizine carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 used on the one hand with the compound of preparation example 13.
Elemental microanalysis:
Rotatory power: (α) d 20=+111.4 ° (c=6mg/mL, MeOH)
embodiment 59:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 13, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+116.8 ° (c=5mg/mL, MeOH)
embodiment 60:n-(1-ethyl-1H-indoles-5-yl)-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 13, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-ethyl-1H-indoles-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 61:n-(4-hydroxy phenyl)-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 13, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl-5-indoline amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 46h 43n 5o 6
[M+H] +calculated value: 762.3292
[M+H] +measured value: 762.3284
embodiment 62:n-(4-hydroxy phenyl)-N-(1-sec.-propyl-1H-indoles-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 13, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-sec.-propyl-1H-indoles-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis: (theoretical value 1.3HCl)
embodiment 63:n-(1-ethyl-2,3-dihydro-1H-indoles-5-yl)-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 13, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-ethyl-5-indoline amine to replace step C preparation example 1 used " compound.
Elemental microanalysis: (theoretical value 1.3HCl)
embodiment 64:n-(4-hydroxy phenyl)-N-(1-sec.-propyl-2,3-dihydro-1H-indoles-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 13, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-sec.-propyl-5-indoline amine to replace step C preparation example 1 used " compound.
Elemental microanalysis: (theoretical value 1.3HCl)
embodiment 65:the chloro-2-[((3S of 3-{5-)-3-[(4-methyl isophthalic acid-piperazinyl) methyl]-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-1-indolizine methane amide two (hydrochloride)
The method is as the method for embodiment 1, on the one hand replace respectively the compound of steps A preparation example used 1 and 1 ' with the compound of preparation example 14 and 3 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine replacement step C preparation example 1 used " compound.
Elemental microanalysis: (theoretical value 1.9HCl)
embodiment 66:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-1-indolizine methane amide two (hydrochloride)
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 14, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl-5-indoline amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+142.2 ° (c=3.5mg/mL, MeOH)
embodiment 67:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 14, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+133.3 ° (c=3.5mg/mL, MeOH)
embodiment 68:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-fluorophenyl)-N-(1-Methyl-1H-indole-5-yl)-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 14, and use on the other hand N-(4-fluorophenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound, should be understood that step D is restricted to the formation step of hydrochloride.
Elemental microanalysis:
embodiment 69:n-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-6-quinolyl)-3-{7-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl }-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 15, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid, 2,3,4-tetrahydrochysene-6-quinolyl amine replaces step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 48h 47n 5o 6
[M+H] +calculated value: 790.3605
[M+H] +measured value: 790.3591
embodiment 70:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{7-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl }-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 15, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 71:n-(4-hydroxy phenyl)-3-{5-methoxyl group-2-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(1-Methyl-1H-indole-5-yl)-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 16, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 46h 43n 5o 5
[M+H] +calculated value: 746.3342
[M+H] +measured value: 746.3348
embodiment 72:8-{[4-hydroxyl (1-Methyl-1H-indole-5-yl) anilino] carbonyl }-6-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-3,4-pyrrolin is [1,2-a] pyrazine-2 (1H)-t-butyl formate also
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 17, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound, should be understood that thus obtained product does not carry out salt formation step under ether solution of hydrogen chloride exists.
Elemental microanalysis:
embodiment 73:8-{[4-hydroxyl (1-methyl-2,3-dihydro-1H-indoles-5-yl) anilino] carbonyl }-6-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-3,4-pyrrolin is [1,2-a] pyrazine-2 (1H)-t-butyl formate also
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 17, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl-5-indoline amine to replace step C preparation example 1 used " compound, should be understood that thus obtained product does not carry out salt formation step under ether solution of hydrogen chloride exists.
Elemental microanalysis:
embodiment 74:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-6-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine-8-methane amide two (hydrochlorides) also
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 17, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound, should be understood that thus obtained product do not carry out as described in embodiment 1 step D under ether solution of hydrogen chloride exists salt formation step.Under the existence of thus obtained compound trifluoroacetic acid in methylene dichloride (10mL/mmol) at 10 equivalents, spend the night at envrionment temperature deprotection.Then, product separates to dry by concentrated reaction mixture subsequently.Finally carry out salt formation step under ether solution of hydrogen chloride exists.
Elemental microanalysis: (theoretical value 1.9HCl)
embodiment 75:n-(4-hydroxy phenyl)-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-6-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1,2,3,4-Pyrrolidine is [1,2-a] pyrazine-8-methane amide three (hydrochlorides) also
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 17, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl-5-indoline amine to replace step C preparation example 1 used " compound, should be understood that thus obtained product do not carry out as described in embodiment 1 step D under ether solution of hydrogen chloride exists salt formation step.Under the existence of thus obtained compound trifluoroacetic acid in methylene dichloride (10mL/mmol) at 10 equivalents, spend the night at envrionment temperature deprotection.Then, product separates to dry by concentrated reaction mixture subsequently.Finally carry out salt formation step under ether solution of hydrogen chloride exists.
Elemental microanalysis:
embodiment 76:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5-{6-[((3S)-3-[(4-methyl isophthalic acid-piperazinyl) methyl]-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-2,3-dihydro-1H-pyrrolizine-7-methane amide two (hydrochlorides)
The method is as the method for embodiment 1, on the one hand replace respectively the compound of steps A preparation example used 1 and 1 ' with the compound of preparation example 18 and 3 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine replacement step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 46h 46n 6o 5
[M+H] +calculated value: 763.3608
[M+H] +measured value: 763.3594
embodiment 77:the chloro-2-[((3S of 5-{5-)-3-[(4-methyl isophthalic acid-piperazinyl) methyl]-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-2,3-dihydro-1H-pyrrolizine-7-methane amide two (hydrochlorides)
The method is as the method for embodiment 1, on the one hand replace respectively the compound of steps A preparation example used 1 and 1 ' with the compound of preparation example 19 and 3 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine replacement step C preparation example 1 used " compound.
Elemental microanalysis: (theoretical value 1.9HCl)
embodiment 78:the chloro-2-[((3S of 6-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-phenyl-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 used with the compound of preparation example 20.
Elemental microanalysis:
embodiment 79:the chloro-2-[((3S of 6-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(2,3-dihydro-1H-indoles-5-yl)-N-(4-hydroxy phenyl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-methane amide two (hydrochloride)
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 20, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-5-indoline amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 80:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-6-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-methane amide
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 21, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound, should be understood that thus obtained product does not carry out salt formation step under ether solution of hydrogen chloride exists.
Elemental microanalysis:
embodiment 81:n-(4-hydroxy phenyl)-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-6-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 21, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl-5-indoline amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 82:the chloro-2-[((3S of 6-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(the fluoro-4-aminomethyl phenyl of 3-)-N-(4-hydroxy phenyl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 20, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) the fluoro-4-monomethylaniline of-3-to replace step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+35.0 ° (c=6mg/mL, MeOH)
embodiment 83:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-6-yl)-6,7,8,9-tetrahydrochysene-5H-pyrrolo-[1,2-a] azepine -1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 22, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 46h 46 35clN 5o 4
[M+H] +calculated value: 768.3317
[M+H] +measured value: 768.3254
embodiment 84:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-6-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-6,7,8,9-tetrahydrochysene-5H-pyrrolo-[1,2-a] azepine -1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 23, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
Rotatory power: (α) d 20=+86.6 ° (c=8mg/mL, MeOH)
embodiment 85:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(3-thienyl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3-thiophenine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 86:the chloro-2-[((3S of 6-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 20, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 44h 42 35clN 5o 5
[M+H] +calculated value: 756.2953
[M+H] +measured value: 756.2936
embodiment 87:n-butyl-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, with N-butyl-4-{[tertiary butyl (dimethyl) silyl] oxygen base aniline replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 88:n-butyl-N-[(3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine base) methyl]-1-butylamine hydrochloride
The method is as the method for embodiment 1, and with N, N-dibutylamine replaces step C preparation example 1 used " compound, should be understood that step D is limited to hydrochloride and forms step.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 39h 50n 4o 5
[M+H] +calculated value: 655.3859
[M+H] +measured value: 655.3826
embodiment 89:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(3-hydroxypropyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 3-{[tertiary butyl (dimethyl) silyl] oxygen base } propyl group)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 90:the chloro-2-[((3S of 3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxybutyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 3-{[tertiary butyl (dimethyl) silyl] oxygen base } butyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 91:n-(the fluoro-4-aminomethyl phenyl of 3-)-3-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 4, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) the fluoro-4-monomethylaniline of-3-to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 92:n-(the fluoro-4-aminomethyl phenyl of 3-)-N-(4-hydroxy phenyl)-6-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 21, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) the fluoro-4-monomethylaniline of-3-to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 93:3-(the chloro-2-{[(3R of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, on the one hand replace steps A preparation example 1 used and 1 ' compound with the compound of preparation example 3 and 2 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 94:n-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replaces step C preparation example 1 used with N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-indazole-5-amine " compound.
Elemental microanalysis:
embodiment 95:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-(5-methyl-2-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 25, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 96:n-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-2,3-dihydro-1H-pyrrolizine-7-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 18, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 97:n-(the chloro-4-aminomethyl phenyl of 3-)-3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) the chloro-4-monomethylaniline of-3-to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 98:n-(the fluoro-4-aminomethyl phenyl of 3-)-6-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 26, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) the fluoro-4-monomethylaniline of-3-to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 42h 40f 2n 4o 5
[M+H] +calculated value: 719.3045
[M+H] +measured value: 719.3030
embodiment 99:6-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-fluorophenyl)-N-(4-hydroxy phenyl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 26, and use on the other hand the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(4-fluorophenyl) aniline replaces step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 41h 38f 2n 4o 5
[M+H] +calculated value: 705.2889
[M+H] +measured value: 705.2882
embodiment 100:3-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-7-hydroxy-n-(4-hydroxy phenyl)-N-phenyl-5,6,7,8-indolizine-1-carboxamide hydrochloride
steps A: 3 '-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-5 ', 6 '-dihydro-8 ' H-spiral shell [DOX-2,7 '-indolizine]-1 '-methyl-formiate
The method, as the method for the steps A of embodiment 1, replaces the compound of preparation example 1 with the compound of preparation example 27.
step B:3-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-7-(third-2-alkene-1-base oxygen base)-5,6,7,8-indolizine-1-methyl-formiate
The method is as the method for the step B of embodiment 13, C and D.
step C:n-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-phenyl-7-(third-2-alkene-1-base oxygen base)-5,6,7,8-indolizine-1-methane amide
The method is as the method for the step B of embodiment 1 and C.
step D:n-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-phenyl-7-hydroxyl-5,6,7,8-indolizine-1-methane amide
Subsequently in methyl alcohol and dichloromethane mixture 1; 3-dimethyl pyrimidine-2,4,6 (1H; 3H, 5H) carry out allylic deprotection reaction under the existence of-triketone (also referred to as barbituric acid dimethyl ester) and tetrakis triphenylphosphine palladium.
step e:3-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-7-hydroxy-n-(4-hydroxy phenyl)-N-phenyl-5,6,7,8-indolizine-1-carboxamide hydrochloride
The deprotection of tertiary butyl silyl oxygen base is to carry out according to the method for the step D of embodiment 1.
Elemental microanalysis:
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 42h 42fN 4o 5
[M+H] +calculated value: 701.3139
[M+H] +measured value: 701.3134
embodiment 101:6-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 20, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-indazole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 102:(2R)-5-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-2-hydroxy-n-(4-hydroxy phenyl)-N-phenyl-2,3-dihydro-1H-pyrrolizine-7-carboxamide hydrochloride
steps A: (the 2R)-2-{[tertiary butyl (dimethyl) silyl] oxygen base }-5-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-2,3-dihydro-1H-pyrrolizine-7-methyl-formiate
The method, as the method for the steps A of embodiment 1, replaces the compound of preparation example 1 with the compound of preparation example 28.
step B:(2R)-5-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-2-hydroxyl-2,3-dihydro-1H-pyrrolizine-7-methyl-formiate
To the compound (1g of steps A; In THF (8mL) solution 1.54mmol), add 1M tetrabutyl ammonium fluoride solution (1.7mL; 1.7mmol).Reaction mixture is stirred 3 hours in envrionment temperature, and then THF is removed in evaporation, and replaces by ethyl acetate.Organic phase is washed with water, then use salt water washing, afterwards through MgSO 4dry, filter and be concentrated into dry.The crude product (830mg) obtaining is directly used in next step.
1h-NMR: δ (500MHz; Dmso-d6; 300 ° of K) 7.55-6.9 (m, 7H, H aromatics); 6.55-6.35 (m, 1H, piperazine in H aromatics pyrrolin); (5.5-5.3 m, 1H, alcohol); 5.25-4.6 (m, 1H, the tertiary tetrahydroisoquinoline of H); 5.0-4.2 (m, 2H, H aliphatics tetrahydroisoquinoline); (4.95-4.62 m, 1H, HCOH); (3.7-3.6 sl, 3H, OMe); 3.6-3.2. (m, 2H, 2H, piperazine in H aliphatics pyrrolin); 3.7-3.5 (m, 4H, H morpholine); 3.0-2.4 (m, 2H, H aliphatics tetrahydroisoquinoline); 2.6-1.96 (m, 4H, H morpholine); 2.6-1.96 (m, 2H, piperazine in H aliphatics pyrrolin)
step C:(2R)-5-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-2-(third-2-alkene-1-base oxygen base)-2,3-dihydro-1H-pyrrolizine-7-methyl-formiate
To being cooled to the compound (820mg that adds step B in the anhydrous THF suspension of 8mL of 62mg (1.54mmol) sodium hydride of 0 DEG C; THF (6mL) solution 1.54mmol).Suspension is stirred 15 minutes at 0 DEG C.Drip subsequently 0.15mL (1.69mmol) allyl bromide 98.Reaction mixture is stirred 5 hours in envrionment temperature, then with saturated sodium bicarbonate aqueous solution hydrolysis, and use dichloromethane extraction.By organic phase through MgSO 4dry, filter and be concentrated into dry.Thus obtained oily matter, by purification by flash chromatography (gradient: methylene dichloride/containing the methyl alcohol of ammonia), is obtained to the title product of solid form.
1h-NMR: δ (500MHz; Dmso-d6; 300 ° of K): 7.5-6.8 (m, 7H, H aromatics); 6.55-6.3 (m, 1H, piperazine in H aromatics pyrrolin); 5.9 (s, 1H, H allyl groups); 5.3-5.2 (m, 2H, H allyl group); 5.2-5.0 (m, 1H, the tertiary tetrahydroisoquinoline of H); 5.0-4.2 (m, 2H, H aliphatics indolizine); 4.7-4.42 (m, 1H, HCO allyl group); 4.6-3.85 (m, 2H, piperazine in H aliphatics pyrrolin); 4.6-3.85 (m, 2H, CH2 allylic); 3.7-3.5 (m, 3H, OMe); 3.65-3.5 (m, 4H, morpholine); 3.3-2.4 (m, 4H, morpholine and H aliphatics pyrrolin alkane); 2.4-1.7 (m, 6H, morpholine and CH 2n)
step D:(2R)-N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-5-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-phenyl-2-(third-2-alkene-1-base oxygen base)-2,3-dihydro-1H-pyrrolizine-7-methane amide
The method is as the method for the step B of embodiment 1 and C.
step e:(2R)-N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-5-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-2-hydroxy-n-phenyl-2,3-dihydro-1H-pyrrolizine-7-methane amide
Then in 1,3-dimethyl pyrimidine-2,4; under the existence of 6 (1H, 3H, 5H)-triketones (also referred to as barbituric acid dimethyl ester) and tetrakis triphenylphosphine palladium, carry out allylic deprotection reaction (Synlett; 2007,21, p.3136).
step F:(2R)-5-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-2-hydroxy-n-(4-hydroxy phenyl)-N-phenyl-2,3-dihydro-1H-pyrrolizine-7-carboxamide hydrochloride
The deprotection of tertiary butyl silyl oxygen base is to carry out according to the method for the step D of embodiment 1.
Elemental microanalysis:
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 41fH 39n 4o 5
[M+H] +calculated value: 687.2983
[M+H] +measured value: 687.2958
embodiment 103:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridine-5-yl)-5,6,7,8-indolizine-1-methane amide
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-pyrrolo-[2,3-b] pyridin-5-amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 44clH 44n 6o 4
[M+H] +calculated value: 755.3113
[M+H] +measured value: 755.3088
embodiment 104:n-(4-hydroxy phenyl)-3-(5-methoxyl group-2-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 6, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-indazole-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 105:n-(4-hydroxy phenyl)-3-(6-{[(3S)-3-{[4-(2-methoxy ethyl) piperazine-1-yl] methyl }-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-methane amide, two (hydrochlorides)
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 ' used with the compound of preparation example 9 '.
Elemental microanalysis:
embodiment 106:(2S)-5-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-2-hydroxy-n-(4-hydroxy phenyl)-N-phenyl-2,3-dihydro-1H-pyrrolizine-7-carboxamide hydrochloride
The method, as the method for embodiment 102, replaces the compound of steps A preparation example 28 used with the compound of preparation example 29.
Elemental microanalysis:
embodiment 107:3-(the chloro-2-{[(3S of 5-)-3-[(4-methyl-3-oxo piperazine-1-yl) methyl]-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, on the one hand replace respectively the compound of steps A preparation example used 1 and 1 ' with the compound of preparation example 3 and 10 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine replacement step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 108:3-(the chloro-2-{[(3S of 5-)-3-{[(2-methoxy ethyl) (methyl) amino] methyl }-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, on the one hand replace respectively the compound of steps A preparation example used 1 and 1 ' with the compound of preparation example 3 and 11 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine replacement step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 109:n-(4-hydroxy phenyl)-3-(6-{[(3S)-3-[(4-morpholine oxide-4-yl) methyl]-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-methane amide
To the 10mL CH of the compound of the embodiment 1 of free alkali form 2cl 2in solution, add m-chlorine peroxybenzoic acid (0.242mg in batches; 1.4mmol).Entirety is stirred and spent the night in envrionment temperature subsequently.Reaction mixture is concentrated into dry subsequently, then by residue by anti-phase purification by flash chromatography (gradient: acetonitrile/water/trifluoroacetic acid).After concentrated, obtain the title product of solid form.
Elemental microanalysis:
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 43h 42n 4o 7
[M+H] +calculated value: 727.3132
[M+H] +measured value: 727.3110
embodiment 110:3-(the chloro-2-{[(3S of 5-)-3-{[ethyl (2-methoxy ethyl) amino] methyl }-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, on the one hand replace respectively the compound of steps A preparation example used 1 and 1 ' with the compound of preparation example 3 and 12 ', and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-Methyl-1H-indole-5-amine replacement step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 111:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-fluorophenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(4-fluorophenyl) aniline replaces step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 42h 40clN 4o 4
[M+H] +calculated value: 719.2722
[M+H] +measured value: 719.2806
embodiment 112:n-(4-hydroxy phenyl)-3-(5-methoxyl group-2-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-phenyl-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 used with the compound of preparation example 6.
Elemental microanalysis:
embodiment 113:7-hydroxy-n-(4-hydroxy phenyl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-carboxamide hydrochloride
steps A: 3 '-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-5 ', 6 '-dihydro-8 ' H-spiral shell [1,3-dioxolane-2,7 '-indolizine]-1 '-methyl-formiate
The method, as the method for the steps A of embodiment 1, replaces the compound of preparation example 1 with the compound of preparation example 30.
step B:3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-7-oxo-5,6,7,8-indolizine-1-methyl-formiate
By the 75mL THF solution of the compound of 2.75g steps A (4.47mmol) stirring and refluxing 15 hours under 37mL1MHCl exists.In reaction mixture, add 100mL water and 100mL ethyl acetate.Add subsequently the 4g NaHCO of powder type 3(4.7mmol), until reach alkaline pH.Compound is extracted with ethyl acetate, by organic phase through MgSO 4dry, filter and be concentrated into dry.Title product is to obtain with oily matter form.
1h-NMR: δ (500MHz; Dmso-d6; 300 ° of K): 7.9-7.2 (m, 4H, H aromatics); 7.02 (m, 1H, H aromatics); 6.88 (m, 1H, H aromatics); 6.44-5.87 (m, 1H, H aromatics indolizine); 6.17 (d, 2H, CH 2methylene radical dioxy base); (5.07/4.85/3.79 m, 1H, the tertiary tetrahydroisoquinoline of H); (4.88/4.27/4.24 m, 2H, H aliphatics tetrahydroisoquinoline); (4.22-3.43 m, 4H, H aliphatics indolizine); (3.59-3.49 m, 4H, H aliphatics morpholine); (3.75-3.52 s, 3H, Me); (2.93-2.49 m, 2H, H aliphatics indolizine); (2.75-2.28 m, 2H, H aliphatics indolizine); 2.68-1.68 (m, 6H, H aliphatics morpholine+CH 2)
step C:7-hydroxyl-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-5,6,7,8-indolizine-1-methyl-formiate
In the 30mL methanol solution of the compound (4.47mmol) obtaining to 2.55g step B, add 558mg (14.75mmol) sodium borohydride in batches.Reaction mixture is stirred 1 hour in envrionment temperature.Add subsequently 50mL1M HCl, and methyl alcohol is removed in evaporation.Water is used NaHCO subsequently 3neutralization, then uses dichloromethane extraction.Organic phase is used H successively 2o washing, through MgSO 4dry, filter and be concentrated into dry.Thus obtained oily matter is passed through to purification by flash chromatography (methylene dichloride/ethanol-ammonia gradient).Title product is to obtain with solid form.
1h-NMR: δ (500MHz; Dmso-d6; 300 ° of K): 7.22-6.97 (m, 4H, H aromatics tetrahydroisoquinoline); 7.05 (s, 1H, H aromatics); 6.89 (s, 1H, H aromatics); 6.37/6.3/6.07 (m, 1H, H aromatics indolizine); 6.16 (d, 2H, CH 2methylene radical dioxy base); 5.09 (m, 1H, the tertiary tetrahydroisoquinolines of H); 4.87-4.21 (m, 2H, H aliphatics indolizine); 4.20-3.67 (m, 2H, H aliphatics indolizine); 4.10-3.86 (m, 1H, the tertiary indolizine of H); (3.69-3.58 s, 3H, Me); 3.69-3.52 (m, 4H, H aliphatics morpholine); 2.96+2.43 (m, 2H, H aliphatics tetrahydroisoquinoline); 2.55-2.0 (m, 6H, H aliphatics morpholine+CH 2); 2.4-1.5 (m, 4H, H aliphatics indolizine)
IR:OH:3239cm -1;-C=O (ester): 1696cm -1;-C=O (acid amides): 1624cm -1; C-C-OH (secondary alcohol): 1034cm -1
step D:3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-7-(third-2-alkene-1-base oxygen base)-5,6,7,8-indolizine-1-methyl-formiate
To being cooled to the compound that adds 2.37g (4.13mmol) step C to obtain in the anhydrous THF suspension of 15mL of 331mg (8.26mmol) sodium hydride of 0 DEG C.Suspension is stirred 15 minutes at 0 DEG C, then slowly add the 10mL THF solution (going through 15 minutes) of 790 μ L (9.1mmol) allyl bromide 98s.Reaction mixture is stirred 1 hour at 0 DEG C, then stir 15 hours in envrionment temperature.The saturated NH of solution 4cl aqueous hydrolysis.Compound is extracted with ethyl acetate; Organic phase is through MgSO 4dry, filter and be concentrated into dry.Thus obtained oily matter is passed through to purification by flash chromatography (cyclohexane/ethyl acetate gradient).Title product is to obtain with solid form.
1h-NMR: δ (500MHz; Dmso-d6; 300 ° of K): 7.2-6.9 (m, 4H, H aromatics tetrahydroisoquinoline); (7.2-6.8 m, 2H, H aromatics); 6.4-6.0 (m, 1H, H aromatics indolizine); 6.10 (d, 2H, CH 2methylene radical dioxy base); 5.9 (m, 1H, allyl groups); (5.35-5.10 m, 2H, allyl group); 5.1+4.75 (m, 1H, the tertiary tetrahydroisoquinoline of H); 4.15-3.9 (m, 2H, CH 2allyl group); 3.9-3.6 (m, 1H, the tertiary indolizine of H); 4.1-3.4 (m, 4H, H aliphatics morpholine); 4.9-3.4 (m, 4H, 2H aliphatics indolizine+2H aliphatics tetrahydroisoquinoline); 3.8-3.6 (s, 3H, Me); 2.55-1.6 (m, 6H, H aliphatics morpholine+CH 2); 3.3-1.5 (m, 6H, 4H aliphatics indolizine+2H aliphatics tetrahydroisoquinoline)
step e:n-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-7-(third-2-alkene-1-base oxygen base)-5,6,7,8-indolizine-1-methane amide
The method is as the method for the step B of embodiment 1 and C.
step F:n-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-7-hydroxyl-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-methane amide
In in methyl alcohol and dichloromethane mixture 1,3-dimethyl pyrimidine-2, carry out allylic deprotection reaction under the existence of 4,6 (1H, 3H, 5H)-triketones (barbituric acid dimethyl ester) and tetrakis triphenylphosphine palladium.
step G:7-hydroxy-n-(4-hydroxy phenyl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-carboxamide hydrochloride
The deprotection of silyl oxygen base is to carry out according to the method for the step D of embodiment 1.
Elemental microanalysis:
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 43h 43n 4o 7
[M+H] +calculated value: 727.3132
[M+H] +measured value: 727.3121
embodiment 114:n-(the fluoro-4-aminomethyl phenyl of 3-)-N-(4-hydroxy phenyl)-3-(5-methoxyl group-2-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 6, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) the fluoro-4-monomethylaniline of-3-to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 115:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(2-fluorophenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(2-fluorophenyl) aniline replaces step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 42h 40clN 4o 4
[M+H] +calculated value: 719.2722
[M+H] +measured value: 719.2802
embodiment 116:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(3-fluorophenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(3-fluorophenyl) aniline replaces step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 42h 40clN 4o 4
[M+H] +calculated value: 719.2722
[M+H] +measured value: 719.2819
embodiment 117:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(2,4-difluorophenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-2,4 difluorobenzene amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 42h 39clF 2n 4o 4
[M+H] +calculated value: 737.2628
[M+H] +measured value: 737.2660
embodiment 118:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(3,4-difluorophenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3,4-difluoroaniline replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 119:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(3-cyano-phenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand the 3-[(4-{[tertiary butyl (dimethyl) silyl] oxygen base phenyl) amino] benzonitrile replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 120:n-(4-hydroxy phenyl)-6-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenylpyrrole also [1,2-a]-pyrazine-8-carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 used with the compound of preparation example 31.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 42h 37n 5o 6
[M+H] +calculated value: 708.2822
[M+H] +measured value: 708.2788
embodiment 121:n-(3-fluorophenyl)-N-(4-hydroxy phenyl)-6-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl) pyrrolo--[1,2-a] pyrazine-8-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 31, and use on the other hand the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(3-fluorophenyl) aniline replaces step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 42h 36fN 5o 6
[M+H] +calculated value: 726.2728
[M+H] +measured value: 726.2723
embodiment 122:n-(3-fluorophenyl)-N-(4-hydroxy phenyl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, with the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(3-fluorophenyl) aniline replaces step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 43h 41fN 4o 6
[M+H] +calculated value: 729.3088
[M+H] +measured value: 729.3068
embodiment 123:n-(4-hydroxy phenyl)-3-(6-{[(3S)-3-{[4-(methyl sulphonyl) piperazine-1-yl] methyl }-3; 4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1; 3-benzo dioxole-5-yl)-N-phenyl-5; 6; 7,8-indolizine-1-carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 ' used with the compound of preparation example 13 '.
Elemental microanalysis:
embodiment 124:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(3-p-methoxy-phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3-anisidine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 125:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(3,5-difluorophenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3,5-difluoroaniline replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 126:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(3-aminomethyl phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3-monomethylaniline to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 127:n-(4-hydroxy phenyl)-N-phenyl-3-(6-{[(3S)-3-{[4-(2,2,2-trifluoroethyl) piperazine-1-yl] methyl }-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 ' used with the compound of preparation example 14 '.
Elemental microanalysis:
embodiment 128:n-(4-hydroxy phenyl)-3-(6-{[(3S)-3-[(4-methyl-3-oxo piperazine-1-yl) methyl]-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 ' used with the compound of preparation example 10 '.
Elemental microanalysis:
embodiment 129:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-cyano-phenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand the 4-[(4-{[tertiary butyl (dimethyl) silyl] oxygen base phenyl) amino] benzonitrile replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 130:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N, N-phenylbenzene-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replaces on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and replaces step C preparation example 1 used with N-phenylaniline on the other hand " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 42h 40cl 2n 4o 4
[M+H] +calculated value: 735.2427
[M+H] +measured value: 735.2524
embodiment 131:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(3-chloro-phenyl-)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3-chloroaniline to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 132:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(pyrimidine-2-base)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) pyrimidine-2-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 133:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(cyclobutylmethyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(cyclobutylmethyl) aniline replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 134:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(2-cyano-phenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand the 2-[(4-{[tertiary butyl (dimethyl) silyl] oxygen base phenyl) amino] benzonitrile replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 135:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-pyrazoles-4-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-pyrazoles-4-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 136:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(cyclopropyl methyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(cyclopropyl methyl) aniline replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 137:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-pyrazole-3-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-pyrazoles-3-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 138:n-(fourth-2-alkynes-1-yl)-3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand the 4-{[tertiary butyl (dimethyl) silyl] oxygen base-N-(fourth-2-alkynes-1-yl) aniline replaces step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 139:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(pyridine-2-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) pyridine-2-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 140:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(pyridazine-3-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) pyridazine-3-amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 42h 39clN 6o 4
[M+H] +calculated value: 703.2721
[M+H] +measured value: 703.2783
embodiment 141:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(pyrimidine-5-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) pyrimidine-5-amine to replace step C preparation example 1 used " compound.
Elemental microanalysis:
embodiment 142:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(pyridin-3-yl)-5,6,7,8-indolizine-1-methane amide, two (hydrochlorides)
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) pyridine-3-amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 41h 40clN 5o 4
[M+H] +calculated value: 702.2769
[M+H] +measured value: 702.2858
embodiment 143:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(3, the fluoro-4-p-methoxy-phenyl of 5-bis-)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3, the fluoro-4-anisidine of 5-bis-replaces step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 43h 41clF 2n 4o 5
[M+H] +calculated value: 767.2734
[M+H] +measured value: 767.2804
embodiment 144:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(pyridin-4-yl)-5,6,7,8-indolizine-1-methane amide, two (hydrochlorides)
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) pyridine-4-amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 41h 40clN 5o 4
[M+H] +calculated value: 702.2842
[M+H] +measured value: 702.2842
embodiment 145:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(the fluoro-4-p-methoxy-phenyl of 3-)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) the fluoro-4-anisidine of-3-to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 43h 42clFN 4o 5
[M+H] +calculated value: 749.2828
[M+H] +measured value: 749.2878
embodiment 146:n-(4-hydroxy phenyl)-3-(6-{[(3S)-3-{[(2-methoxy ethyl) (methyl) amino] methyl }-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 ' used with the compound of preparation example 11 '.
Elemental microanalysis:
embodiment 147:3-(6-{[(3S)-3-[(1,1-titanium dioxide thiomorpholine-4-yl) methyl]-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-(4-hydroxy phenyl)-N-phenyl-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation 1 ' used with the compound of preparation example 15 '.
Elemental microanalysis:
embodiment 148:n-(5-hydroxy pyrimidine-2-yl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-methane amide trifluoroacetate
steps A: N-[5-(benzyl oxygen base) pyrimidine-2-base]-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-methane amide
The method is as the steps A of the method for embodiment 1, B and C, replaces step C preparation example 1 used with 5-(benzyl oxygen base)-N-phenyl pyrimidine-2-amine " compound.
step B: N-(5-hydroxy pyrimidine-2-yl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-methane amide trifluoroacetate
By the compound (150mg of steps A; 0.2mmol) be dissolved in 8mL methyl alcohol, and add 30mg Pd/C (10% palladium weight).Reaction mixture is stirred 15 hours hydrogen atmosphere (1.2 bar) is lower, then filter through Whatman filter, vacuum concentration and by reverse-phase chromatography purifying (gradient: acetonitrile/water, under the existence of trifluoroacetic acid).Required product is to obtain with trifluoroacetic acid salt form.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 41h 40n 6o 6
[M+H] +calculated value: 713.3082
[M+H] +measured value: 713.3080
embodiment 149:n-(4-hydroxy phenyl)-3-(6-{[(3S)-3-[(3-methoxyl group pyrrolidin-1-yl) methyl]-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 ' used with the compound of preparation example 16 '.
Elemental microanalysis:
embodiment 150:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(3-cyano group-4-p-methoxy-phenyl)-N-(4-hydroxy phenyl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand the 5-[(4-{[tertiary butyl (dimethyl) silyl] oxygen base phenyl) amino]-2-HOMOVERATRONITRILE replaces step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 44h 42clN 5o 5
[M+H] +calculated value: 756.2874
[M+H] +measured value: 756.2917
embodiment 151:n-(4-hydroxy phenyl)-3-(5-methoxyl group-2-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(1-methyl isophthalic acid H-pyrazoles-4-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 6, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-pyrazoles-4-amine to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 41h 44n 6o 5
[M+H] +calculated value: 701.3446
[M+H] +measured value: 701.3446
embodiment 152:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-[3-(trifluoromethyl) phenyl]-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 3, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-3-(trifluoromethyl) aniline to replace step C preparation example 1 used " compound.
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 43h 40clF 3n 4o 4
[M+H] +calculated value: 769.2690
[M+H] +measured value: 769.2718
embodiment 153:3-(6-{[(3S)-3-[(3,3-difluoro pyrrolidin-1-yl) methyl]-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-(4-hydroxy phenyl)-N-phenyl-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 ' used with the compound of preparation example 17 '.
Elemental microanalysis:
embodiment 154:n-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-pyrazoles-4-yl)-3-(7-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 7, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-pyrazoles-4-amine to replace step C preparation example 1 used " compound.
embodiment 155:n-(4-hydroxy phenyl)-3-(7-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl)-N-(pyrimidine-5-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 7, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl) pyrimidine-5-amine to replace step C preparation example 1 used " compound.
embodiment 156:n-(4-hydroxy phenyl)-3-(6-{[(3S)-3-[(3-methoxyl group azetidine-1-yl) methyl]-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-phenyl-5,6,7,8-indolizine-1-methane amide
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 ' used with the compound of preparation example 18 '.
Elemental microanalysis:
High Resolntion Mass-Spectrometry (ESI+):
Empirical formula: C 43h 42n 4o 6
[M+H] +calculated value: 711.3177
[M+H] +measured value: 711.3178
embodiment 157:3-(6-{[(3S)-3-[(3-fluorine azetidine-1-yl) methyl]-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-N-(4-hydroxy phenyl)-N-phenyl-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method, as the method for embodiment 1, replaces the compound of steps A preparation example 1 ' used with the compound of preparation example 19.
embodiment 158:3-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-pyrazoles-4-yl)-5,6,7,8-indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 4, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-pyrazoles-4-amine to replace step C preparation example 1 used " compound.
embodiment 159:3-(the fluoro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-pyrazoles-4-yl) indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 32, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-pyrazoles-4-amine to replace step C preparation example 1 used " compound.
embodiment 160:3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-pyrazoles-4-yl) indolizine-1-carboxamide hydrochloride
The method is as the method for embodiment 1, replace on the one hand the compound of steps A preparation example 1 used with the compound of preparation example 14, and use on the other hand N-(the 4-{[tertiary butyl (dimethyl) silyl] oxygen base } phenyl)-1-methyl isophthalic acid H-pyrazoles-4-amine to replace step C preparation example 1 used " compound.
pharmaceutical research
embodiment A: the inhibition of fluorescence polarization technology research Bcl-2
Fluorescence polarization test is to carry out on microwell plate (384 hole).By final concentration 2.50 × 10 -8the Bcl-2 protein of M and final concentration 1.00 × 10 -8the fluorescence peptide (fluorescein-REIGAQLRRMADDLNAQY) of M mixes in the damping fluid (Hepes10mM, NaCl150mM, Tween200.05%, pH7.4) of test compound that contains or do not contain rising concentration.After incubation 2 hours, measure fluorescence polarization.
Result is with IC 50(suppressing the compound concentration of 50% fluorescence polarization) represents, and following table 1 has provided result.
Result shows that the compounds of this invention suppresses the interaction of Bcl-2 protein and above-mentioned fluorescence peptide.
embodiment B: vitro cytotoxicity
Study of cytotoxicity is at RS4; 11 leukemia tumours are fastened and are carried out.
Cell distribution, on microwell plate, and is exposed to test compound 48 hours.Then by colorimetric analysis, trace cultivate the quantitative cell viability of tetrazolium analytical method (Cancer Res., 1987, 47, 939-942).
Result is with IC 50(suppressing the compound concentration of 50% cell viability) represents, and following table 1 has provided result.
Result shows that the compounds of this invention has cytotoxicity.
the IC that table 1:Bcl-2 suppresses 50 (fluorescence polarization test) and to RS4; The cytotoxicity of 11 cells
embodiment C: induction Caspase activity in body
The ability of the compounds of this invention activation caspase 3 is at RS4; In 11 leukemia cells' heteroplastic transplantation model, assess.
By 1 × 10 7rS4; 11 cell subcutaneous transplantations are in immunosuppressant mouse (SCID kind).Transplant the oral processing of different compounds for animal latter 25 to 30 days.Process latter 16 hours, reclaim tumor mass and cracking, and in Tumor lysis, measure Caspase activity.
This enzyme measurement is that the fluorescence generation split product (DEVDase activity, Promega) occurring by analysis carries out.It is to represent corresponding to the activation factor form of ratio between two kinds of Caspase activity: the activity of the mouse of processing is divided by the activity of control mice.
Table 2 has provided the result obtaining, and result shows induction RS4 in the compounds of this invention energy body; Apoptosis in 11 tumour cells.
table 2: after oral processing in (bracket in accurately dosage) body Caspase activation factor (processing dEVDase activity in the tumour of mouse and control mice)
embodiment D: in body, the caspase 3 of cracking form is quantitative
The ability of the compounds of this invention activation caspase 3 is at RS4; In 11 leukemia cells' heteroplastic transplantation model, assess.
By 1 × 10 7rS4; 11 cell subcutaneous transplantations are in immunosuppressant mouse (SCID kind).Transplant the oral processing of different compounds for animal latter 25 to 30 days.After processing, reclaim tumor mass and cracking, and in Tumor lysis the caspase 3 of quantitative cleavage (activation) form.
Quantitatively carry out the caspase 3 of its specificity analyses cracking form with " Meso Scale Discovery (MSD) ELISA platform " test.It is to represent divided by the activation factor form of ratio between the amount of the caspase 3 of the cracking of control mice with the amount of the caspase 3 of the cracking corresponding to the mouse of processing.
Table 3 has provided the result obtaining, and result shows induction RS4 in the compounds of this invention energy body; Apoptosis in 11 tumour cells.
table 3: after oral processing in (bracket in accurately dosage) body Caspase activation factor (processing the caspase 3 MSD test of cracking in the tumour of mouse and control mice)
embodiment E: anti-tumor in vivo activity
The anti-tumor activity of the compounds of this invention is at RS4; In 11 leukemia cells' heteroplastic transplantation model, assess.
By 1 × 10 7rS4; 11 cell subcutaneous transplantations are in immunosuppressant mouse (SCID kind).Transplant latter 25 to 30 days, when tumor mass reaches 150mm 3time, the oral processing of different compounds of two kinds of different schemes for mouse (5 days weekly, process every day, continuous two weeks; Or process weekly twice, continuous two weeks).Processing beginning twice measurement tumor mass weekly.
Oral by way of the compounds of this invention at RS4; In 11 Leukemia Models (acute lymphoblastic leukemia), there is anti-tumor activity, Δ T/C (the qualification parameter of its lytic activity, it be defined as the ratio of the gross tumor volume of the gross tumor volume/untreated control group of the treatment group) scope from-15 to-56% relevant to tumor regression.Thus obtained result shows that the compounds of this invention can disappear by remarkable induced tumor during processing.
Embodiment F: pharmaceutical composition: tablet
Comprise dosage and be 1000 tablet 5g of the compound that 5mg is selected from embodiment 1 to 160
Wheat starch 20g
W-Gum 20g
Lactose 30g
Magnesium Stearate 2g
Silica 1 g
Hydroxypropylcellulose 2g

Claims (24)

1. formula (I) compound, their enantiomer and diastereomer, and with the additive salt of pharmaceutically acceptable acid or alkali:
Wherein:
◆ X and Y represent carbon atom or nitrogen-atoms, should be understood that they can not represent two carbon atoms or two nitrogen-atoms simultaneously,
◆ group het part represent aromatics or the non-aromatic ring of the optional replacement being formed by 5,6 or 7 ring memberses, except the nitrogen that X or Y represent, it can comprise 1 to 3 heteroatoms independently selected from oxygen, sulphur and nitrogen, should be understood that described nitrogen can be by (the C of hydrogen atom, linearity or branch 1-C 6) alkyl or group that group-C (O)-O-Alk represents replace, wherein Alk is linearity or the (C of branch 1-C 6) alkyl,
◆ R 1and R 2represent independently of one another (the C of hydrogen atom or linearity or branch 1-C 6) alkyl,
Or R 1and R 2form by 4 to 7 Heterocyclylalkyls that ring members forms with the nitrogen-atoms with them, except nitrogen-atoms, it can comprise other oxygen, sulphur, the SO of being selected from 2with the heteroatoms of NR, wherein R represents the (C of hydrogen atom, linearity or branch 1-C 6) alkyl, (C 1-C 6) (the C of alkyl sulphonyl, linearity or branch 1-C 6) multi-haloalkyl or group-C (O)-O-Alk, wherein Alk is linearity or the (C of branch 1-C 6) alkyl,
◆ R 3represent (the C of linearity or branch 1-C 6) alkyl, (C 2-C 6) alkenyl, (C 2-C 6) alkynyl, cycloalkyl, (C 4-C 10) cycloalkyl-(C 1-C 6) alkyl, wherein alkyl can be linear or branch, aryl or heteroaryl,
◆ R 4represent (the C of aryl, heteroaryl, cycloalkyl or linearity or branch 1-C 6) alkyl,
◆ R 5represent hydrogen atom or halogen atom,
◆ R a, R b, R cand R drepresent independently of one another (the C of hydrogen atom, halogen atom, linearity or branch 1-C 6) (the C of alkyl, linearity or branch 1-C 6) (the C of alkoxyl group, hydroxyl, linearity or branch 1-C 6) multi-haloalkyl or trifluoromethoxy, or paired (R a, R b), (R b, R c) or (R c, R d) one of substituting group form by 5 to 7 rings that ring members forms with together with carbon atom with them, it can comprise 1 to 3 heteroatoms that is selected from oxygen, sulphur and nitrogen, should be understood that described nitrogen can be by (the C of hydrogen atom, linearity or branch 1-C 6) alkyl or group that group-C (O)-O-Alk represents replace, wherein Alk is linearity or the (C of branch 1-C 6) alkyl, the one or more carbon atoms that should be understood that ring defined above can be deuterates,
Should be understood that:
-" aryl " represents phenyl, naphthyl, xenyl or indenyl,
-" heteroaryl " represents any monocycle or the bicyclic groups that are made up of 5 to 10 ring memberses, there is at least one aromatics part and comprise 1 to 3 heteroatoms that is selected from oxygen, sulphur and nitrogen,
-" cycloalkyl " represents any monocycle or the non-aromatic carbon ring group of two rings that comprise 4 to 10 ring memberses,
It is possible being replaced by 1 to 3 group for defined alkyl, aryl, heteroaryl, cycloalkyl and Heterocyclylalkyl, and described group is selected from the linearity of optional replacement or the (C of branch 1-C 6) alkyl, (C 3-C 6) (the C of volution, linearity or branch 1-C 6) alkoxyl group, (C 1-C 6) alkyl-S-, hydroxyl, oxo (or suitably N-oxide compound), nitro, cyano group ,-COOR ', NR ' R ", (C of linearity or branch 1-C 6) multi-haloalkyl, trifluoromethoxy, (C 1-C 6) alkyl sulphonyl or halogen, should be understood that R ' and R " represent independently of one another (the C of hydrogen atom or linearity or branch 1-C 6) alkyl,
For group defined above het part to be replaced by group be possible, described group is selected from the (C of linearity or branch 1-C 6) alkyl, hydroxyl, NR 1' R 1" and halogen, should be understood that R 1' and R 1" with radicals R mentioned above ' and R " there is identical definition.
2. the formula of claim 1 (I) compound, wherein group represent one of following groups: optionally replaced by hydroxyl 5,6,7,8-indolizine, indolizine, 1,2,3,4-Pyrrolidine is [1,2-a] pyrazine, 3 also, 4-pyrrolin also [1,2-a] pyrazine-2 (1H)-t-butyl formate, 3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine, optionally replaced by hydroxyl 2,3-dihydro-1H-pyrrolizine, 6,7,8,9-tetrahydrochysene-5H-pyrrolo-[1,2-a] azepine or pyrrolo-[1,2-a] pyrazine.
3. the formula of claim 1 (I) compound, wherein R 1and R 2represent optionally by the alkyl of methoxy substitution separately, or R 1and R 2form Heterocyclylalkyl with the nitrogen-atoms with them, be selected from following groups: optionally by the (C of one or more linearities or branch 1-C 6) alkyl replace morpholine, morpholine oxide, thiomorpholine, 1,1-dioxide, 1,4-oxa-azepan, 3-methoxyl group tetramethyleneimine, 3,3-bis-fluoropyrrolidines, 3-methoxyl group azetidine, 3-fluorine azetidine, oxo piperazine or piperazine, latter two group is by linearity or the (C of branch 1-C 6) (the C of alkyl, linearity or branch 1-C 6) multi-haloalkyl or methyl sulphonyl replacement.
4. the formula of claim 1 (I) compound, wherein R aand R drepresent separately hydrogen atom, and (R b, R c) forming DOX group with together with carbon atom with them, one of them carbon atom is optionally deuterate, Isosorbide-5-Nitrae-dioxane group, Isosorbide-5-Nitrae-Dioxepane group, or R a, R cand R drepresent separately hydrogen atom, and R brepresent halogen, methyl, methoxyl group, oxyethyl group, trifluoromethyl or trifluoromethoxy.
5. the formula of claim 1 (I) compound, wherein R 4represent 4-hydroxy phenyl, the fluoro-4-hydroxy phenyl of 3-or 5-hydroxy pyrimidine group.
6. the formula of claim 1 (I) compound, wherein R 3represent to be selected from following group: phenyl, indoles, indoline, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzo piperazine, indane, 1H-indazole, 1H-pyrrolo-[2,3-b] pyridine, pyrimidine, cyclobutylmethyl, cyclopropyl methyl, 1H-pyrazoles, pyridine, pyridazine, those groups optionally have one or more substituting groups, and described substituting group is selected from the (C of halogen, linearity or branch 1-C 6) (the C of alkyl, cyano group and linearity or branch 1-C 6) alkoxyl group.
7. the formula of claim 1 (I) compound, it is selected from:
-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
The chloro-2-[((3S of-3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-3-{2,2-bis-deuteriums-6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-5,6,7,8-indolizine-1-methane amide
-N-(4-hydroxy phenyl)-3-{7-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine methane amide,
-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-[(4-methyl isophthalic acid-piperazinyl) methyl]-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine methane amide
-N-[4-(hydroxyl) phenyl]-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-1-indolizine methane amide
The chloro-2-[((3S of-3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-1-indolizine methane amide
The chloro-2-[((3S of-6-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(the fluoro-4-aminomethyl phenyl of 3-)-N-(4-hydroxy phenyl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-methane amide,
-3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-pyrazoles-4-yl)-5,6,7,8-indolizine-1-methane amide
-N-(the fluoro-4-aminomethyl phenyl of 3-)-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-[4-(hydroxyl) phenyl]-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
The chloro-2-[((3S of-3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine methane amide
The chloro-2-[((3S of-3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-methyl-2,3-dihydro-1H-indoles-5-yl)-1-indolizine methane amide
The chloro-2-[((3S of-6-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-phenyl-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-methane amide,
-N-(3-fluorophenyl)-N-(4-hydroxy phenyl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-5,6,7,8-indolizine-1-methane amide
Their enantiomer and diastereomer, with and with the additive salt of pharmaceutically acceptable acid or alkali.
8. the formula of claim 1 (I) compound, it is selected from:
-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
The chloro-2-[((3S of-3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-3-{2,2-bis-deuteriums-6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-indazole-5-yl)-3-(6-{[(3S)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl }-1,3-benzo dioxole-5-yl)-5,6,7,8-indolizine-1-methane amide
-N-(4-hydroxy phenyl)-3-{7-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-2,3-dihydro-Isosorbide-5-Nitrae--benzo two alkene-6-yl }-N-phenyl-5,6,7,8-tetrahydrochysene-1-indolizine methane amide,
-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-[(4-methyl isophthalic acid-piperazinyl) methyl]-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-1-indolizine methane amide
-N-[4-(hydroxyl) phenyl]-N-(1-Methyl-1H-indole-5-yl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-5,6,7,8-tetrahydrochysene-1-indolizine methane amide
-N-(4-hydroxy phenyl)-3-{6-[((3S)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl]-1,3-benzo dioxole-5-yl }-N-phenyl-1-indolizine methane amide
The chloro-2-[((3S of-3-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(4-hydroxy phenyl)-N-(1-Methyl-1H-indole-5-yl)-1-indolizine methane amide
The chloro-2-[((3S of-6-{5-)-3-(4-morpholinyl methyl)-3,4-dihydro-2 (1H)-isoquinolyl) carbonyl] phenyl }-N-(the fluoro-4-aminomethyl phenyl of 3-)-N-(4-hydroxy phenyl)-3,4-dihydro-1H-pyrrolo-[2,1-c] [Isosorbide-5-Nitrae] piperazine-8-methane amide,
-3-(the chloro-2-{[(3S of 5-)-3-(morpholine-4-ylmethyl)-3,4-dihydro-isoquinoline-2 (1H)-yl] carbonyl } phenyl)-N-(4-hydroxy phenyl)-N-(1-methyl isophthalic acid H-pyrazoles-4-yl)-5,6,7,8-indolizine-1-methane amide
Their enantiomer and diastereomer, with and with the additive salt of pharmaceutically acceptable acid or alkali.
9. the method for formula (I) compound of preparation claim 1, is characterized in that formula (II) compound is used as raw material:
Wherein R a, R b, R cand R dit is defined suc as formula (I),
Formula (II) compound carries out Heck reaction in moisture or organic medium under the existence of palladium catalyst, alkali, phosphine and formula (III) compound:
Wherein radicals X, Y and Het are defined suc as formula (I),
Obtain formula (IV) compound:
Wherein R a, R b, R c, R d, X, Y and Het defined suc as formula (I),
The aldehyde functional group of formula (IV) compound is oxidized to carboxylic acid, forms formula (V) compound:
Wherein R a, R b, R c, R d, X, Y and Het defined suc as formula (I),
Then, formula (V) compound and formula (VI) compound carry out peptide coupling:
Wherein R 1, R 2and R 5it is defined suc as formula (I),
Obtain formula (VII) compound:
Wherein R a, R b, R c, R d, R 1, R 2, R 5, X, Y and Het defined suc as formula (I),
By the ester functional group hydrolysis of formula (VII) compound, obtain carboxylic acid or corresponding carboxylate salt, with amine NHR 3r 4, wherein R 3and R 4have the implication identical with formula (I), before coupling, can be translated into acid derivative, for example acyl chlorides or corresponding acid anhydrides, obtain formula (I) compound,
Formula (I) compound can be according to conventional isolation technique purifying, if needed, itself and pharmaceutically acceptable acid or alkali is converted into additive salt, and the isomer that is it by its optionally separating according to conventional isolation technique,
Should be understood that, in the process of aforesaid method, be considered to suitable in, some group (hydroxyl, the amino of initial reagent or synthetic intermediate ...) can be according to synthetic needs protected and deprotection subsequently.
10. the method for the claim 9 of preparation formula (I) compound, wherein radicals R 3and R 4one of replaced by hydroxy functional group, it is characterized in that with the carboxylic acid of formula (VII) compound formation or its corresponding acid derivative coupling before amine NHR 3r 4carry out in advance the protective reaction of hydroxy functional group, formula (I) compound of the protection of generation carries out deprotection reaction subsequently, is then optionally converted into one of additive salt with pharmaceutically acceptable acid or alkali.
11. pharmaceutical compositions, the additive salt of formula (I) compound that this pharmaceutical composition comprises claim 1 to 8 any one or itself and pharmaceutically acceptable acid or alkali, and one or more pharmaceutically acceptable vehicle.
The pharmaceutical composition of 12. claims 11, it is as short apoptosis agent.
The pharmaceutical composition of 13. claims 11, it is used for the treatment of cancer and treatment immunity and autoimmune disease.
The pharmaceutical composition of 14. claims 11, it is used for the treatment of bladder cancer, the cancer of the brain, breast cancer and uterus carcinoma, chronic lymphoid leukemia, colorectal carcinoma, esophagus cancer and liver cancer, lymphoblast leukemia, follicular lymphoma, melanoma, malignant hematologic disease, myelomatosis, ovarian cancer, nonsmall-cell lung cancer, prostate cancer and small cell lung cancer.
The pharmaceutical composition of 15. claims 11 is used as the purposes in the medicine of urging apoptosis agent in preparation.
The purposes of the pharmaceutical composition of 16. claims 11 in the medicine for the preparation for the treatment of cancer and treatment immunity and autoimmune disease.
The purposes of the pharmaceutical composition of 17. claims 11 in the medicine for the preparation for the treatment of bladder cancer, the cancer of the brain, breast cancer and uterus carcinoma, chronic lymphoid leukemia, colorectal carcinoma, esophagus cancer and liver cancer, lymphoblast leukemia, follicular lymphoma, melanoma, malignant hematologic disease, myelomatosis, ovarian cancer, nonsmall-cell lung cancer, prostate cancer and small cell lung cancer.
The additive salt of formula (I) compound of 18. claim 1 to 8 any one or itself and pharmaceutically acceptable acid or alkali, it is used for the treatment of bladder cancer, the cancer of the brain, breast cancer and uterus carcinoma, chronic lymphoid leukemia, colorectal carcinoma, esophagus cancer and liver cancer, lymphoblast leukemia, follicular lymphoma, melanoma, malignant hematologic disease, myelomatosis, ovarian cancer, nonsmall-cell lung cancer, prostate cancer and small cell lung cancer.
The purposes of the additive salt of formula (I) compound of 19. claim 1 to 8 any one or itself and pharmaceutically acceptable acid or alkali in the medicine for the preparation for the treatment of bladder cancer, the cancer of the brain, breast cancer and uterus carcinoma, chronic lymphoid leukemia, colorectal carcinoma, esophagus cancer and liver cancer, lymphoblast leukemia, follicular lymphoma, melanoma, malignant hematologic disease, myelomatosis, ovarian cancer, nonsmall-cell lung cancer, prostate cancer and small cell lung cancer.
Formula (I) compound of 20. claim 1 to 8 any one and the combined prod of carcinostatic agent, described carcinostatic agent is selected from genotoxic promoting agent, mitotic division poisonous substance, antimetabolite, proteasome inhibitor, kinase inhibitor and antibody.
21. pharmaceutical compositions, the combined prod that this pharmaceutical composition comprises claim 20 and one or more pharmaceutically acceptable vehicle.
The combined prod of 22. claims 20, it is used for the treatment of cancer.
The purposes of the combined prod of 23. claims 20 in the medicine for the preparation for the treatment of cancer.
Formula (I) compound of 24. claim 1 to 8 any one, its for radiotherapy treatment of cancer with combinations.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107922432A (en) * 2015-06-23 2018-04-17 法国施维雅药厂 New hydroxy-acid derivative, its preparation method and the pharmaceutical composition containing them

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2986002B1 (en) 2012-01-24 2014-02-21 Servier Lab NOVEL INDOLIZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
FR3008977A1 (en) * 2013-07-23 2015-01-30 Servier Lab NOVEL ISOINDOLINE OR ISOQUINOLINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
FR3008976A1 (en) * 2013-07-23 2015-01-30 Servier Lab "NOVEL INDOLIZINE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"
FR3008975A1 (en) * 2013-07-23 2015-01-30 Servier Lab NOVEL PYRROLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
FR3008979B1 (en) 2013-07-23 2015-07-24 Servier Lab NOVEL PHOSPHATE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
FR3008978A1 (en) * 2013-07-23 2015-01-30 Servier Lab "NOVEL INDOLE AND PYRROLE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"
FR3015483B1 (en) * 2013-12-23 2016-01-01 Servier Lab NOVEL THIENOPYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
US20150320755A1 (en) 2014-04-16 2015-11-12 Infinity Pharmaceuticals, Inc. Combination therapies
WO2016190847A1 (en) * 2015-05-26 2016-12-01 Calitor Sciences, Llc Substituted heteroaryl compounds and methods of use
FR3037959B1 (en) * 2015-06-23 2017-08-04 Servier Lab NOVEL BICYCLIC DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
FR3037956B1 (en) * 2015-06-23 2017-08-04 Servier Lab NOVEL AMINO ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
WO2017013271A1 (en) * 2015-07-23 2017-01-26 Les Laboratoires Servier Combination of an inhibitor of phosphatidylinositol 3-kinase delta and a bcl-2 inhibitor, uses and pharmaceutical compositions thereof
UY37316A (en) 2016-07-07 2018-01-31 Servier Lab SOLID PHARMACEUTICAL DISPERSION OF A BCL-2 INHIBITOR, PHARMACEUTICAL COMPOSITIONS OF THIS, AND USES FOR CANCER TREATMENT
TWI759316B (en) 2016-07-22 2022-04-01 法商施維雅藥廠 Combination of a bcl-2 inhibitor and a mcl1 inhibitor, uses and pharmaceutical compositions thereof
WO2018158225A1 (en) 2017-02-28 2018-09-07 Les Laboratoires Servier Combination of a bcl-2 inhibitor and a mdm2 inhibitor, uses and pharmaceutical compositions thereof
AR112440A1 (en) * 2017-07-06 2019-10-30 Servier Lab CRYSTAL FORM OF A BCL-2 INHIBITOR, A PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT
CA3070004A1 (en) 2017-07-27 2019-01-31 Jiangsu Hengrui Medicine Co., Ltd. Piperazine heteroaryl derivative, preparation method therefor and use of same in medicine
FR3072679B1 (en) * 2017-10-25 2020-10-30 Servier Lab NEW MACROCYCLIC DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO2019134970A1 (en) 2018-01-05 2019-07-11 Les Laboratoires Servier Novel salts of a bcl-2 inhibitor,related crystalline forms,method for preparing the same and pharmaceutical compositions containing the same
BR112020016551A2 (en) 2018-02-16 2020-12-22 Abbvie Inc. SELECTIVE BCL-2 INHIBITORS IN COMBINATION WITH ANTI-PD-1 OR ANTI-PD-L1 ANTIBODY FOR CANCER TREATMENT
PL3969000T3 (en) 2019-05-14 2024-02-26 Les Laboratoires Servier Bcl-2 inhibitors for use in the treatment of a bcl-2 mediated cancer carrying the gly101val mutation
KR20220017931A (en) 2019-05-20 2022-02-14 노파르티스 아게 MCL-1 inhibitor antibody-drug conjugates and methods of use
WO2022115451A1 (en) 2020-11-24 2022-06-02 Novartis Ag Mcl-1 inhibitor antibody-drug conjugates and methods of use
CN117794929A (en) 2021-02-02 2024-03-29 法国施维雅药厂 Selective BCL-XL PROTAC compounds and methods of use
JP2024508948A (en) * 2021-03-12 2024-02-28 エイル セラピューティクス，インコーポレイテッド Compounds with tetrahydroindolizine-1-carboxamide as BCL-2 inhibitors
TW202408588A (en) 2022-05-20 2024-03-01 瑞士商諾華公司 Antibody-drug conjugates of antineoplastic compounds and methods of use thereof
AR129382A1 (en) 2022-05-20 2024-08-21 Novartis Ag BCL-XL AND MET INHIBITORS ANTIBODY-DRUG CONJUGATES AND THEIR METHODS OF USE
WO2023225320A1 (en) 2022-05-20 2023-11-23 Novartis Ag Epha2 bcl-xl inhibitor antibody-drug conjugates and methods of use thereof
WO2024189481A1 (en) 2023-03-10 2024-09-19 Novartis Ag Panras inhibitor antibody-drug conjugates and methods of use thereof

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5932590A (en) * 1996-12-05 1999-08-03 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
CN100391958C (en) * 2001-09-19 2008-06-04 安万特医药股份有限公司 Chemical compounds
AU2003234464B2 (en) * 2002-05-03 2009-06-04 Exelixis, Inc. Protein kinase modulators and methods of use
US20050070570A1 (en) 2003-06-18 2005-03-31 4Sc Ag Novel potassium channels modulators
WO2006023778A2 (en) 2004-08-20 2006-03-02 The Regents Of The University Of Michigan Small molecule inhibitors of anti-apoptotic bcl-2 family members and the uses thereof
AU2008242983B2 (en) * 2007-04-16 2013-07-11 Abbvie Inc. 7-substituted indole Mcl-1 inhibitors
CN102007101A (en) 2007-11-30 2011-04-06 生物区科学管理控股有限公司 Tetrahydro-isoquinoline ppat inhibitors as antibacterial agents
US20090297897A1 (en) 2007-12-07 2009-12-03 Robert Walter Boyd Methods for monitoring hydrogen fueling systems
AU2009215191A1 (en) 2008-02-13 2009-08-20 Gilead Connecticut, Inc. 6-aryl-imidaz0[l, 2-a] pyrazine derivatives, method of making, and method of use thereof
US20120095211A1 (en) 2010-09-22 2012-04-19 Intermune, Inc. Substituted proline inhibitors of hepatitis c virus replication
WO2012162365A1 (en) * 2011-05-25 2012-11-29 Bristol-Myers Squibb Company Substituted sulfonamides useful as antiapoptotic bcl inhibitors
FR2986002B1 (en) * 2012-01-24 2014-02-21 Servier Lab NOVEL INDOLIZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
FR3008976A1 (en) 2013-07-23 2015-01-30 Servier Lab "NOVEL INDOLIZINE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
J. PORTER ET AL.: "Tetrahydroisoquinoline amide substituted phenyl pyrazoles", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
JOHN PORTER ET AL: "Atropisomeric small molecule Bcl-2 ligands: Determination", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107922432A (en) * 2015-06-23 2018-04-17 法国施维雅药厂 New hydroxy-acid derivative, its preparation method and the pharmaceutical composition containing them
CN107922432B (en) * 2015-06-23 2021-05-04 法国施维雅药厂 Novel hydroxy acid derivatives, process for their preparation and pharmaceutical compositions containing them

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